α- and β-amino acid hydroxyethylamino sulfonamides useful as retroviral protease inhibitors

ABSTRACT

alpha - and  beta -amino acid hydroxyethylamino sulfonamide compounds are effective as retroviral protease inhibitors, and in particular as inhibitors of HIV protease.

RELATED APPLICATION

This application is a continuation in part application of co-owned andPCT/US93/07814, filed Aug. 24, 1993, which is a continuation in partapplication of co-owned U.S. patent application Ser. No. 07/934,984filed Aug. 25, 1992, now abandoned.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to retroviral protease inhibitors and,more particularly, relates to novel compounds and a composition andmethod for inhibiting retroviral proteases. This invention, inparticular, relates to sulfonamide-containing hydroxyethylamine proteaseinhibitor compounds, a composition and method for inhibiting retroviralproteases such as human immunodeficiency virus (HIV) protease and fortreating a retroviral infection, e.g., an HIV infection. The subjectinvention also relates to processes for making such compounds as well asto intermediates useful in such processes.

2. Related Art

During the replication cycle of retroviruses, gag and gag-pol geneproducts are translated as proteins. These proteins are subsequentlyprocessed by a virally encoded protease (or proteinase) to yield viralenzymes and structural proteins of the virus core. Most commonly, thegag precursor proteins are processed into the core proteins and the polprecursor proteins are processed into the viral enzymes, e.g., reversetranscriptase and retroviral protease. It has been shown that correctprocessing of the precursor proteins by the retroviral protease isnecessary for assembly of infectious virons. For example, it has beenshown that frameshift mutations in the protease region of the pol geneof HIV prevents processing of the gag precursor protein. It has alsobeen shown through site-directed mutagenesis of an aspartic acid residuein the HIV protease that processing of the gag precursor protein isprevented. Thus, attempts have been made to inhibit viral replication byinhibiting the action of retroviral proteases.

Retroviral protease inhibition may involve a transition-state mimeticwhereby the retroviral protease is exposed to a mimetic compound whichbinds to the enzyme in competition with the gag and gag-pol proteins tothereby inhibit replication of structural proteins and, moreimportantly, the retroviral protease itself. In this manner, retroviralreplication proteases can be effectively inhibited.

Several classes of compounds have been proposed, particularly forinhibition of proteases, such as for inhibition of HIV protease. Suchcompounds include hydroxyethylamine isosteres and reduced amideisosteres. See, for example, EP O 346 847; EP O 342,541; Roberts et al,"Rational Design of Peptide-Based Proteinase Inhibitors, "Science, 248,358 (1990); and Erickson et al, "Design Activity, and 2.8Å CrystalStructure of a C₂ Symmetric Inhibitor Complexed to HIV-1 Protease,"Science, 249, 527 (1990).

Several classes of compounds are known to be useful as inhibitors of theproteolytic enzyme renin. See, for example, U.S. Pat. No. 4,599,198;U.K. 2,184,730; G.B. 2,209,752; EP O 264 795; G.B. 2,200,115 and U.S.SIR H725. Of these, G.B. 2,200,115, GB 2,209,752, EP O 264,795, U.S. SIRH725 and U.S. Pat. No. 4,599,198 disclose urea-containinghydroxyethylamine renin inhibitors. EP 468 641 discloses renininhibitors and intermediates for the preparation of the inhibitors,which include sulfonamide-containing hydroxyethylamine compounds, suchas3-(t-butoxycarbonyl)amino-cyclohexyl-1-(phenylsulfonyl)amino-2(5)-butanol.G.B. 2,200,115 also discloses sulfamoyl-containing hydroxyethylaminerenin inhibitors, and EP 0264 795 discloses certainsulfonamide-containing hydroxyethylamine renin inhibitors. However, itis known that, although renin and HIV proteases are both classified asaspartyl proteases, compounds which are effective renin inhibitorsgenerally cannot be predicted to be effective HIV protease inhibitors.

BRIEF DESCRIPTION OF THE INVENTION

The present invention is directed to virus inhibiting compounds andcompositions. More particularly, the present invention is directed toretroviral protease inhibiting compounds and compositions, to a methodof inhibiting retroviral proteases, to processes for preparing thecompounds and to intermediates useful in such processes. The subjectcompounds are characterized as sulfonamide-containing hydroxyethylamineinhibitor compounds.

DETAILED DESCRIPTION OF THE INVENTION

In accordance with the present invention, there is provided a retroviralprotease inhibiting compound of the formula: ##STR1## or apharmaceutically acceptable salt, prodrug or ester thereof wherein: Rrepresents hydrogen, alkoxycarbonyl, aralkoxycarbonyl, alkylcarbonyl,cycloalkylcarbonyl, cycloalkylalkoxycarbonyl, cycloalkylalkanoyl,alkanoyl, aralkanoyl, aroyl, aryloxycarbonyl, aryloxycarbonylalkyl,aryloxyalkanoyl, heterocyclylcarbonyl, heterocyclyloxycarbonyl,heterocyclylalkanoyl, heterocyclylalkoxycarbonyl, heteroaralkanoyl,heteroaralkoxycarbonyl, heteroaryloxycarbonyl, heteroaroyl, alkyl,alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, aryloxyalkyl,heteroaryloxyalkyl, hydroxyalkyl, aminocarbonyl, aminoalkanoyl, andmono- and disubstituted aminocarbonyl and mono- and disubstitutedaminoalkanoyl radicals wherein the substituents are selected from alkyl,aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroaralkyl,heterocycloalkyl, heterocycloalkyalkyl radicals, or where saidaminocarbonyl and aminoalkanoyl radicals are disubstituted, saidsubstituents along with the nitrogen atom to which they are attachedform a heterocycloalkyl or heteroaryl radical;

R' represents hydrogen, radicals as defined for R³ or R"SO₂ -wherein R"represents radicals as defined for R³ ; or R and R' together with thenitrogen to which they are attached represent heterocycloalkyl andheteroaryl radicals;

R¹ represents hydrogen, --CH₂ SO₂ NH₂, --CH₂ CO₂ CH₃, --CO₂ CH₃,--CONH₂, --CH₂ C(O)NHCH₃, --C(CH ₃)₂ (SH), --C(CH₃)₂ (SCH₃), --C(CH₃)₂(S[O]CH₃), --C(CH₃)₂ (S[O]₂ CH₃), alkyl, haloalkyl, alkenyl, alkynyl andcycloalkyl radicals, and amino acid side chains selected fromasparagine, S-methyl cysteine and the sulfoxide (SO) and sulfone (SO₂)derivatives thereof, isoleucine, allo-isoleucine, alanine, leucine,tert-leucine, phenylalanine, ornithine, histidine, norleucine,glutamine, threonine, glycine, allothreonine, serine, O-alkyl serine,aspartic acid, beta-cyano alanine and valine side chains;

R¹ ' and R¹ " independently represent hydrogen and radicals as definedfor R¹, or one of R¹ ' and R¹ ", together with R¹ and the carbon atomsto which R¹, R¹ ' and R¹ " are attached, represent a cycloalkyl radical;

R² represents alkyl, aryl, cycloalkyl, cycloalkylalkyl and aralkylradicals, which radicals are optionally substituted with a groupselected from alkyl and halogen radials, --NO₂, --CN, --CF₃, --OR⁹ and--SR⁹, wherein R⁹ represents hydrogen and alkyl radicals, and halogenradicals;

R³ represents hydrogen, alkyl, haloalkyl, alkenyl, alkynyl,hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl,heterocycloalkyl, heteroaryl, heterocycloalkylalkyl, aryl, aralkyl,heteroaralkyl, aminoalkyl and mono- and disubstituted aminoalkylradicals, wherein said substituents are selected from alkyl, aryl,aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroaralkyl,heterocycloalkyl, and heterocycloalkylalkyl radicals, or in the case ofa disubstituted aminoalkyl radical, said substituents along with thenitrogen atom to which they are attached, form a heterocycloalkyl or aheteroaryl radical;

R⁴ represents radicals as defined by R³ except for hydrogen;

R⁶ represents hydrogen and alkyl radicals;

x represents 0, 1 or 2;

t represents either 0 or 1; and

Y represents O, S and NR¹⁵ wherein R¹⁵ represents hydrogen and radicalsas defined for R³.

A family of compounds of particular interest within Formula I arecompounds embraced by Formula II: ##STR2## wherein: R representshydrogen, alkoxycarbonyl, aralkoxycarbonyl, alkylcarbonyl,cycloalkylcarbonyl, cycloalkylalkoxycarbonyl, cycloalkylalkanoyl,alkanoyl, aralkanoyl, aroyl, aryloxycarbonyl, aryloxycarbonylalkyl,aryloxyalkanoyl, heterocyclylcarbonyl, heterocyclyloxycarbonyl,heterocyclylalkanoyl, heterocyclylalkoxycarbonyl, heteroaralkanoyl,heteroaralkoxycarbonyl, heteroaryloxy-carbonyl, heteroaroyl, alkyl,alkenyl, cycloalkyl, aryl, aralkyl, aryloxyalkyl, heteroaryloxyalkyl,hydroxyalkyl, aminocarbonyl, aminoalkanoyl, and mono- and disubstitutedaminocarbonyl and mono- and disubstituted aminoalkanoyl radicals whereinthe substituents are selected from alkyl, aryl, aralkyl, cycloalkyl,cycloalkylalkyl, heteroaryl, heteroaralkyl, heterocycloalkyl,heterocycloalkyalkyl radicals, or where said aminoalkanoyl radical isdisubstituted, said substituents along with the nitrogen atom to whichthey are attached form a heterocycloalkyl or heteroaryl radical;

R' represents hydrogen and radicals as defined for R³ or R and R'together with the nitrogen to which they are attached representheterocycloalkyl and heteroaryl radical;

R¹ represents hydrogen, --CH₂ SO₂ NH₂, --CH₂ CO₂ CH₃, --CO₂ CH₃,--CONH₂, --CH₂ C(O)NHCH₃, --C(CH₃ )₂ (SH), --C(CH₃)₂ (SCH₃), --C(CH₃)₂(S[O]CH₃), --C(CH₃)₂ (S[O]₂ CH₃), alkyl, haloalkyl, alkenyl, alkynyl andcycloalkyl radicals, and amino acid side chains selected fromasparagine, S-methyl cysteine and the sulfoxide (SO) and sulfone (SO₂)derivatives thereof, isoleucine, allo-isoleucine, alanine, leucine,tert-leucine, phenylalanine, ornithine, histidine, norleucine,glutamine, threonine, glycine, allo-threonine, serine, O-methyl serine,aspartic acid, beta-cyano alanine and valine side chains;

R² represents alkyl, aryl, cycloalkyl, cycloalkylalkyl and aralkylradicals, which radicals are optionally substituted with a groupselected from alkyl and halogen radials, --NO₂, --C.tbd.N, CF₃, --OR⁹,--SR⁹, wherein R⁹ represents hydrogen and alkyl radicals;

R³ represents alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl,alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heteroaryl,heterocycloalkylalkyl, aryl, aralkyl, heteroaralkyl, aminoalkyl andmono- and disubstituted aminoalkyl radicals, wherein said substituentsare selected from alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl,heteroaryl, heteroaralkyl, heterocycloalkyl, and heterocycloalkylalkylradicals, or in the case of a disubstituted aminoalkyl radical, saidsubstituents along with the nitrogen atom to which they are attached,form a heterocycloalkyl or a heteroaryl radical; and

R⁴ represents radicals as defined by R³.

A more preferred family of compounds within Formula II consists ofcompounds wherein:

R represents hydrogen, alkoxycarbonyl, aralkoxycarbonyl, alkylcarbonyl,cycloalkylcarbonyl, cycloalkylalkoxycarbonyl, cycloalkylalkanoyl,alkanoyl, aralkanoyl, aroyl, aryloxycarbonyl, aryloxycarbonylalkyl,aryloxyalkanoyl, heterocyclylcarbonyl, heterocyclyloxycarbonyl,heterocyclylalkanoyl, heterocyclylalkoxycarbonyl, heteroaralkanoyl,heteroaralkoxycarbonyl, heteroaryloxy-carbonyl, heteroaroyl, alkyl,alkenyl, cycloalkyl, aryl, aralkyl, aryloxyalkyl, heteroaryloxyalkyl,hydroxyalkyl, aminocarbonyl, aminoalkanoyl, and mono- and disubstitutedaminocarbonyl and mono- and disubstituted aminoalkanoyl radicals whereinthe substituents are selected from alkyl, aryl, aralkyl, cycloalkyl,cycloalkylalkyl, heteroaryl, heteroaralkyl, heterocycloalkyl,heterocycloalkyalkyl radicals, or where said aminoalkanoyl radical isdisubstituted, said substituents along with the nitrogen atom to whichthey are attached form a heterocycloalkyl or heteroaryl radical;

R' represents hydrogen and radicals as defined for R³ or R and R'together with the nitrogen to which they are attached representheterocycloalkyl and heteroaryl radical;

R¹ represents CH₂ C(O)NHCH₃, C(CH₃)₂ (SCH₃), C(CH₃)₂ (S[O]CH₃), C(CH₃)₂(S[O]₂ CH₃), alkyl, alkenyl and alkynyl radicals, and amino acid sidechains selected from the group consisting of asparagine, valine,threonine, allo-threonine, isoleucine, tert-leucine, S-methyl cysteineand the sulfone and sulfoxide derivatives thereof, alanine, andallo-isoleucine;

R² represents alkyl, cycloalkylalkyl and aralkyl radicals, whichradicals are optionally substituted with halogen radicals and radicalsrepresented by the formula --OR⁹ and --SR⁹ wherein R⁹ represents alkylradicals; and

R³ and R⁴ independently represent alkyl, alkenyl, alkoxyalkyl,cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl,aryl, aralkyl and heteroaralkyl radicals.

Of highest interest are compounds within Formula II wherein

R represents alkoxycarbonyl, aralkoxycarbonyl, alkylcarbonyl,cycloalkylcarbonyl, cycloalkylalkoxycarbonyl, cycloalkylalkanoyl,alkanoyl, aralkanoyl, aroyl, aryloxycarbonyl, aryloxycarbonylalkyl,aryloxyalkanoyl, heterocyclylcarbonyl, heterocyclyloxycarbonyl,heterocyclylalkanoyl, heterocyclylalkoxycarbonyl, heteroaralkanoyl,heteroaralkoxycarbonyl, heteroaryloxy-carbonyl, heteroaroyl,aminocarbonyl, aminoalkanoyl, and mono- and disubstituted aminocarbonyland mono- and disubstituted aminoalkanoyl radicals wherein thesubstituents are selected from alkyl, aryl, aralkyl, cycloalkyl,cycloalkylalkyl, heteroaryl, heteroaralkyl, heterocycloalkyl,heterocycloalkyalkyl radicals, or where said aminoalkanoyl radical isdisubstituted, said substituents along with the nitrogen atom to whichthey are attached form a heterocycloalkyl or heteroaryl radical;

R' represents hydrogen and radicals as defined for R³ or R and R'together with the nitrogen to which they are attached representheterocycloalkyl and heteroaryl radical;

R¹ represents CH₂ C(O)NHCH₃, C(CH₃)₂ (SCH₃), C(CH₃)₂ (S[O]CH₃), C(CH₃)₂(S[O]₂ CH₃), methyl, propargyl, t-butyl, isopropyl and sec-butylradicals, and amino acid side chains selected from the group consistingof asparagine, valine, S-methyl cysteine, allo-iso-leucine, iso-leucine,and beta-cyano alanine side chains;

R² represents CH₃ SCH₂ CH₂ --, iso-butyl, n-butyl, benzyl,4-fluorobenzyl, 2-naphthylmethyl and cyclohexylmethyl radicals;

R³ represents isoamyl, n-butyl, isobutyl and cyclohexyl radicals; and

R⁴ represents phenyl, substituted phenyl and methyl radicals.

Another family of compounds of particular interest within Formula I arecompounds embraced by Formula III: ##STR3## wherein: R representshydrogen, alkoxycarbonyl, aralkoxycarbonyl, alkylcarbonyl,cycloalkylcarbonyl, cycloalkylalkoxycarbonyl, cycloalkylalkanoyl,alkanoyl, aralkanoyl, aroyl, aryloxycarbonyl, aryloxycarbonylalkyl,aryloxyalkanoyl, heterocyclylcarbonyl, heterocyclyloxycarbonyl,heterocyclylalkanoyl, heterocyclylalkoxycarbonyl, heteroaralkanoyl,heteroaralkoxycarbonyl, heteroaryloxy-carbonyl, heteroaroyl, alkyl,alkenyl, cycloalkyl, aryl, aralkyl, aryloxyalkyl, heteroaryloxyalkyl,hydroxyalkyl, aminocarbonyl, aminoalkanoyl, and mono- and disubstitutedaminocarbonyl and mono- and disubstituted aminoalkanoyl radicals whereinthe substituents are selected from alkyl, aryl, aralkyl, cycloalkyl,cycloalkylalkyl, heteroaryl, heteroaralkyl; heterocycloalkyl,heterocycloalkyalkyl radicals, or where said aminoalkanoyl radical isdisubstituted, said substituents along with the nitrogen atom to whichthey are attached form a heterocycloalkyl or heteroaryl radical;

R' represents hydrogen and radicals as defined for R³ or R and R'together with the nitrogen to which they are attached representheterocycloalkyl and heteroaryl radical;

R¹ represents hydrogen, --CH₂ SO₂ NH₂, --CH₂ CO₂ CH₃, --CO₂ CH₃,--CONH₂, --CH₂ C(O)NHCH₃, --C(CH ₃)₂ (SH), --C(CH₃)₂ (SCH₃), --C(CH₃)₂(S[O]CH₃), --C(CH₃)₂ (S[O]₂ CH₃), alkyl, haloalkyl, alkenyl, alkynyl andcycloalkyl radicals, and amino acid side chains selected fromasparagine, S-methyl cysteine and the sulfoxide (SO) and sulfone (SO₂)derivatives thereof, isoleucine, allo-isoleucine, alanine, leucine,tert-leucine, phenylalanine, ornithine, histidine, norleucine,glutamine, threonine, glycine, allo-threonine, serine, aspartic acid,beta-cyano alanine and valine side chains;

R² represents alkyl, aryl, cycloalkyl, cycloalkylalkyl and aralkylradicals, which radicals are optionally substituted with a groupselected from alkyl and halogen radicals, --NO₂, --C.tbd.N, CF₃, --OR⁹,--SR⁹ ; wherein R⁹ represents hydrogen and alkyl;

R³ represents alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl,alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heteroaryl,heterocycloalkylalkyl, aryl, aralkyl, heteroaralkyl, aminoalkyl andmono- and disubstituted aminoalkyl radicals, wherein said substituentsare selected from alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl,heteroaryl, heteroaralkyl, heterocycloalkyl, and heterocycloalkylalkylradicals, or in the case of a disubstituted aminoalkyl radical, saidsubstituents along with the nitrogen atom to which they are attached,form a heterocycloalkyl or a heteroaryl radical; and

R⁴ represents radicals as defined by R³.

A more preferred family of compounds within Formula III consists ofcompounds wherein

R represents hydrogen, alkoxycarbonyl, aralkoxycarbonyl, alkylcarbonyl,cycloalkylcarbonyl, cycloalkylalkoxycarbonyl, cycloalkylalkanoyl,alkanoyl, aralkanoyl, aroyl, aryloxycarbonyl, aryloxycarbonylalkyl,aryloxyalkanoyl, heterocyclylcarbonyl, heterocyclyloxycarbonyl,heterocyclylalkanoyl, heterocyclylalkoxycarbonyl, heteroaralkanoyl,heteroaralkoxycarbonyl, heteroaryloxy-carbonyl, heteroaroyl, alkyl,alkenyl, cycloalkyl, aryl, aralkyl, aryloxyalkyl, heteroaryloxyalkyl,hydroxyalkyl, aminocarbonyl, aminoalkanoyl, and mono- and disubstitutedaminocarbonyl and mono- and disubstituted aminoalkanoyl radicals whereinthe substituents are selected from alkyl, aryl, aralkyl, cycloalkyl,cycloalkylalkyl, heteroaryl, heteroaralkyl, heterocycloalkyl,heterocycloalkyalkyl radicals, or where said aminoalkanoyl radical isdisubstituted, said substituents along with the nitrogen atom to whichthey are attached form a heterocycloalkyl or heteroaryl radical;

R' represents hydrogen and radicals as defined for R³ or R and R'together with the nitrogen to which they are attached representheterocycloalkyl and heteroaryl radical;

R¹ represents hydrogen, alkyl and alkenyl radicals, and amino acid sidechains selected from the group consisting of asparagine, valine,threonine, allo-threonine, isoleucine, tert-leucine, S-methyl cysteineand the sulfone and sulfoxide derivatives thereof, alanine, andallo-isoleucine;

R² represents alkyl, cycloalkylalkyl and aralkyl radicals, whichradicals are optionally substituted with halogen radicals and radicalsrepresented by the formula --OR⁹ and --SR⁹ wherein R⁹ representshydrogen and alkyl and halogen radicals; and

R³ and R⁴ independently represent alkyl, alkenyl, alkoxyalkyl,cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl,aryl, aralkyl, heteroaryl and heteroaralkyl radicals.

Of highest interest are compounds within Formula III wherein

R represents hydrogen, alkoxycarbonyl, aralkoxycarbonyl, alkylcarbonyl,cycloalkylcarbonyl, cycloalkylalkoxycarbonyl, cycloalkylalkanoyl,alkanoyl, aralkanoyl, aroyl, aryloxycarbonyl, aryloxycarbonylalkyl,aryloxyalkanoyl, heterocyclylcarbonyl, heterocyclyloxycarbonyl,heterocyclylalkanoyl, heterocyclylalkoxycarbonyl, heteroaralkanoyl,heteroaralkoxycarbonyl, heteroaryloxy-carbonyl, heteroaroyl,aminocarbonyl, aminoalkanoyl, and mono- and disubstituted aminocarbonyland mono- and disubstituted aminoalkanoyl radicals wherein thesubstituents are selected from alkyl, aryl, aralkyl, cycloalkyl,cycloalkylalkyl, heteroaryl, heteroaralkyl, heterocycloalkyl,heterocycloalkyalkyl radicals, or where said aminoalkanoyl radical isdisubstituted, said substituents along with the nitrogen atom to whichthey are attached form a heterocycloalkyl or heteroaryl radical;

R' represents hydrogen and radicals as defined for R³ or R and R'together with the nitrogen to which they are attached representheterocycloalkyl and heteroaryl radical;

R¹ represents hydrogen, methyl, propargyl, t-butyl, isopropyl andsec-butyl radicals, and amino acid side chains selected from the groupconsisting of asparagine, valine, S-methyl cysteine, allo-iso-leucine,iso-leucine, threonine, serine, aspartic acid, beta-cyano alanine, andallo-threonine side chains;

R² represents CH₃ SCH₂ CH₂ --, iso-butyl, n-butyl, benzyl,4-fluorobenzyl, 2-naphthylmethyl and cyclohexylmethyl radicals; and

R³ represents alkyl, cyclohexyl, isobutyl, isoamyl, and n-butylradicals; and

R⁴ represents methyl, phenyl and substituted phenyl radicals wherein thesubstituents are selected from halo, alkoxy, hydroxy, nitro and aminosubstituents.

Another family of compounds of particular interest within Formula I arecompounds embraced by Formula IV: ##STR4## wherein: R representshydrogen, alkoxycarbonyl, aralkoxycarbonyl, alkylcarbonyl,cycloalkylcarbonyl, cycloalkylalkoxycarbonyl, cycloalkylalkanoyl,alkanoyl, aralkanoyl, aroyl, aryloxycarbonyl, aryloxycarbonylalkyl,aryloxyalkanoyl, heterocyclylcarbonyl, heterocyclyloxycarbonyl,heterocyclylalkanoyl, heterocyclylalkoxycarbonyl, heteroaralkanoyl,heteroaralkoxycarbonyl, heteroaryloxy-carbonyl, heteroaroyl, alkyl,alkenyl, cycloalkyl, aryl, aralkyl, aryloxyalkyl, heteroaryloxyalkyl,hydroxyalkyl, aminocarbonyl, aminoalkanoyl, and mono- and disubstitutedaminocarbonyl and mono- and disubstituted aminoalkanoyl radicals whereinthe substituents are selected from alkyl, aryl, aralkyl, cycloalkyl,cycloalkylalkyl, heteroaryl, heteroaralkyl, heterocycloalkyl,heterocycloalkyalkyl radicals, or where said aminoalkanoyl radical isdisubstituted, said substituents along with the nitrogen atom to whichthey are attached form a heterocycloalkyl or heteroaryl radical;

R' represents hydrogen and radicals as defined for R³ or R and R'together with the nitrogen to which they are attached representheterocycloalkyl and heteroaryl radical;

R¹ represents hydrogen, --CH₂ SO₂ NH₂, --CH₂ CO₂ CH₃, --CO₂ CH₃,--CONH₂, --CH₂ C(O)NHCH₃, --C(CH₃)₂ (SH), --C(CH₃)₂ (SCH₃), --C(CH₃)₂(S[O]CH₃), --C(CH₃)₂ (S[O]₂ CH₃), alkyl, haloalkyl, alkenyl, alkynyl andcycloalkyl radicals, and amino acid side chains selected fromasparagine, S-methyl cysteine and the sulfoxide (SO) and sulfone (SO₂)derivatives thereof, isoleucine, allo-isoleucine, alanine, leucine,tert-leucine, phenylalanine, ornithine, histidine, norleucine,glutamine, threonine, glycine, allo-threonine, serine, aspartic acid,beta-cyano alanine and valine side chains;

R¹ ' and R¹ " independently represent hydrogen and radicals as definedfor R¹, or one of R¹ ' and R¹ ", together with R¹ and the carbon atomsto which R¹, R¹ ' and R¹ " are attached, represent a cycloalkyl radical;

R² represents alkyl, aryl, cycloalkyl, cycloalkylalkyl and aralkylradicals, which radicals are optionally substituted with a groupselected from alkyl and halogen radials, --NO₂, --C.tbd.N, CF₃, --OR⁹and --SR⁹, wherein R⁹ represents hydrogen and alkyl radicals;

R³ represents alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl,alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heteroaryl,heterocycloalkylalkyl, aryl, aralkyl, heteroaralkyl, aminoalkyl andmono- and disubstituted aminoalkyl radicals, wherein said substituentsare selected from alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl,heteroaryl, heteroaralkyl, heterocycloalkyl, and heterocycloalkylalkylradicals, or in the case of a disubstituted aminoalkyl radical, saidsubstituents along with the nitrogen atom to which they are attached,form a heterocycloalkyl or a heteroaryl radical; and

R⁴ represents radicals as defined by R³.

A more preferred family of compounds within Formula IV consists ofcompounds wherein

R represents an arylalkanoyl, heteroaroyl, aryloxyalkanoyl,aryloxycarbonyl, alkanoyl, aminocarbonyl, mono-substitutedaminoalkanoyl, or disubstituted aminoalkanoyl, or mono-ordialkylaminocarbonyl radical;

R' represents hydrogen and radicals as defined for R³ or R and R'together with the nitrogen to which they are attached represent aheterocycloalkyl or heteroaryl radical;

R¹, R¹ ' and R¹ " independently represent hydrogen and alkyl radicalshaving from 1 to about 4 carbon atoms, alkenyl, alkynyl, aralkylradicals, and radicals represented by the formula --CH₂ C(O)R" or--C(O)R" wherein R" represents R³⁸, --NR³⁸ R³⁹ and OR³⁸ wherein R³⁸ andR³⁹ independently represent hydrogen and alkyl radicals having from 1 toabout 4 carbon atoms;

R² represents alkyl, cycloalkylalkyl and aralkyl radicals, whichradicals are optionally substituted with halogen radicals and radicalsrepresented by the formula --OR⁹ and --SR⁹ wherein R⁹ representshydrogen and alkyl radicals; and

R³ and R⁴ independently represent alkyl, alkenyl, alkoxyalkyl,cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl,aryl, aralkyl, heteroaryl and heteroaralkyl radicals.

Of highest interest are compounds of Formula IV

wherein:

R represents an arylalkanoyl, aryloxycarbonyl, aryloxyalkanoyl,alkanoyl, aminocarbonyl, mono-substituted aminoalkanoyl, ordisubstituted aminoalkanoyl, or mono-or dialkylaminocarbonyl radical;

R' represents hydrogen and radicals as defined for R³ or R and R'together with the nitrogen to which they are attached represent aheterocycloalkyl or heteroaryl radical;

R¹, R¹ ' and R¹ " independently represent hydrogen, methyl, ethyl,benzyl, phenylpropyl and propargyl radicals;

R² represents CH₃ SCH₂ CH₂ --, iso-butyl, n-butyl, benzyl,4-fluorobenzyl, 2-naphthylmethyl and cyclohexylmethyl radicals;

R³ represents alkyl, cyclohexyl, isobutyl, isoamyl and n-butyl radicals;and

R⁴ represents methyl, phenyl and substituted phenyl radicals wherein thesubstituents are selected from halo, alkoxy, amino and nitrosubstituents.

As utilized herein, the term "alkyl", alone or in combination, means astraight-chain or branched-chain alkyl radical containing from 1 toabout 10 carbon atoms, preferably from 1 to about 8 carbon atoms, morepreferably 1-5 carbon atoms. Examples of such radicals include methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl,pentyl, iso-amyl, hexyl, octyl and the like. The term "alkenyl", aloneor in combination, means a straight-chain or branched-chain hydrocarbonradial having one or more double bonds and containing from 2 to about 18carbon atoms, preferably from 2 to about 8 carbon atoms, more preferablyfrom 2 to about 5 carbon atoms. Examples of suitable alkenyl radicalsinclude ethenyl, propenyl, alkyl, 1,4-butadienyl and the like. The term"alkynyl", alone or in combination, means a straight-chain or branchedchain hydrocarbon radical having one or more triple bonds and containingfrom 2 to about 10 carbon atoms, more preferably from 2 to about 5carbon atoms. Examples of alkynyl radicals include ethynyl, propynyl,(propargyl), butynyl and the like. The term "alkoxy", alone or incombination, means an alkyl ether radical wherein the term alkyl is asdefined above. Examples of suitable alkyl ether radicals includemethoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy,sec-butoxy, tert-butoxy and the like. The term "cycloalkyl", alone or incombination, means a saturated or partially saturated monocyclic,bicyclic or tricyclic alkyl radical wherein each cyclic moiety containsfrom about 3 to about 8 carbon atoms, more preferably from about 3 toabout 6 carbon atoms, and is cyclic. Examples of such cycloalkylradicals include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl andthe like. The term "cycloalkylalkyl" means an alkyl radical as definedabove which is substituted by a cycloalkyl radical as defined above. Theterm "aryl", alone or in combination, means a phenyl or naphthyl radicalwhich optionally carries one or more substituents selected from alkyl,alkoxy, halogen, hydroxy, amino, nitro, cyano, haloalkyl, carboxy,alkoxycarbonyl, cycloalkyl, heterocycloalkyl, amido, mono and dialkylsubstituted amino, mono and dialkyl substituted amido and the like, suchas phenyl, p-tolyl, 4-methoxyphenyl, 4-(tert-butoxy)phenyl,4-fluorophenyl, 4-chlorophenyl, 4-hydroxyphenyl, 1-naphthyl, 2-naphthyl,and the like. The terms "aralkyl" and "aralkoxy", alone or incombination, means an alkyl or alkoxy radical as defined above in whichat least one hydrogen atom is replaced by an aryl radical as definedabove, such as benzyl, benzyloxy, 2-phenylethyl, dibenzylmethyl,hydroxyphenylmethyl, methylphenylmethyl, and the like. The term"aralkoxy carbonyl", alone or in combination, means a radical of theformula --C(O)--O--aralkyl in which the term "aralkyl" has thesignificance given above. Examples of an aralkoxycarbonyl radical arebenzyloxycarbonyl and methylphenylmethoxycarbonyl. The term "aryloxyllmeans a radical of the formula aryl--O-- in which the term aryl has thesignificance given above. The term "alkanoyl", alone or in combination,means an acyl radical derived from an alkanecarboxylic acid, examples ofwhich include acetyl, propionyl, butyryl, valeryl, 4-methylvaleryl, andthe like. The term "cycloalkylcarbony", means an acyl group derived froma monocyclic or bridged cycloalkanecarboxylic acid such ascyclopropanecarbonyl, cyclohexanecarbonyl, adamantanecarbonyl, and thelike, or from a benz-fused monocyclic cycloalkanecarboxylic acid whichis optionally substituted by, for example, alkanoylamino, such as1,2,3,4-tetrahydro-2-naphthoyl,2-acetamido-1,2,3,4-tetrahydro-2-naphthoyl. The term "aralkanoyl" meansan acyl radical derived from an aryl-substituted alkanecarboxylic acidsuch as phenylacetyl, 3-phenylpropionyl (hydrocinnamoyl),4-phenylbutyryl, (2-naphthyl)acetyl, 4-chlorohydrocinnamoyl,4-aminohydrocinnamoyl,4-methoxyhydrocinnamoyl, and the like. The term"aroyl" means an acyl radical derived from an aromatic carboxylic acid.Examples of such radicals include aromatic carboxylic acids, anoptionally substituted benzoic or naphthoic acid such as benzoyl,4-chlorobenzoyl, 4-carboxybenzoyl, 4-(benzyloxycarbonyl)benzoyl,1-naphthoyl, 2-naphthoyl, 6-carboxy-2 naphthoyl,6-(benzyloxycarbonyl)-2-naphthoyl, 3-benzyloxy-2-naphthoyl,3-hydroxy-2-naphthoyl, 3-(benzyloxyformamido)-2-naphthoyl, and the like.The terms "heterocyclyl" and "heterocycloalkyl" alone or in combination,mean a saturated or partially unsaturated monocyclic, bicyclic ortricyclic heterocycle which contains one or more heteroatoms selectedfrom nitrogen, oxygen and sulphur, which is optionally substituted onone or more carbon atoms by halogen, alkyl, alkoxy, hydroxy, oxo, aryl,aralkyl and the like, and/or on a secondary nitrogen atom (i.e., --NH--)by hydroxy, alkyl, aralkoxycarbonyl, alkanoyl, phenyl or phenylalkyland/or on a tertiary nitrogen atom (i.e.=N--) by oxido and which isattached via a carbon atom. Heterocycloalkyl and heterocyclyl alsoincludes benz-fused monocyclic cycloalkyl groups having at least oneheteroatom. Heterocycloalkyl and heterocyclyl in addition to sulfur andnitrogen also includes sulfones, sulfoxides and N-oxides of tertiarynitrogen containing heterocycloalkyl groups. The term "heteroaryl",alone or in combination, means an aromatic monocyclic, bicyclic, ortricyclic heterocycle which contains the heteroatoms and is optionallysubstituted as defined above with respect to the definitions of aryl andheterocycloalkyl. Examples of such heterocycloalkyl and heteroarylgroups are pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl,thiamorpholinyl, pyrrolyl, imidazolyl (e.g., imidazol 4-yl,1-benzyloxycarbonylimidazol-4-yl, etc.), pyrazolyl, pyridyl, (e.g.,2-(1-piperidinyl)pyridyl and 2-(4-benzyl piperazin-1-yl-1-pyridinyl),pyrazinyl, pyrimidinyl, furyl, thienyl, triazolyl, oxazolyl, thiazolyl,indolyl (e.g., 2-indolyl, etc.), quinolinyl, (e.g., 2-quinolinyl,3-quinolinyl, 1-oxido-2-quinolinyl, etc.), isoquinolinyl (e.g.,1-isoquinolinyl, 3-isoquinolinyl, etc.), tetrahydroquinolinyl (e.g.,1,2,3,4-tetrahydro-2-quinolyl, etc.), 1,2,3,4-tetrahydroisoquinolinyl(e.g., 1,2,3,4-tetrahydro-1-oxo-isoquinolinyl, etc.), quinoxalinyl,β-carbolinyl, 2-benzofurancarbonyl, 1-, 2-,4- or 5-benzimidazolyl, andthe like. The term "cycloalkylalkoxycarbonyl" means an acyl groupderived from a cycloalkylalkoxycarboxylic acid of the formulacycloalkylalkyl--O--COOH wherein cycloalkylalkyl has the significancegiven above. The term "aryloxyalkanoyl" means an acyl radical of theformula aryl--O--alkanoyl wherein aryl and alkanoyl have thesignificance given above. The term "heterocycloalkoxycarbonyll, means anacyl group derived from heterocyclyl--O--COOH wherein heterocyclyl is asdefined above. The term "heterocycloalkylalkanoyl" is an acyl radicalderived from a heterocycloalkyl-substituted alkane carboxylic acidwherein heterocycloalkyl has the significance given above. The term"heterocycloalkylalkoxycarbonyl" means an acyl radical derived from aheterocycloalkyl-substituted alkane--O--COOH wherein heterocyclyl hasthe significance given above. The term "heteroaryloxycarbonyl" means anacyl radical derived from a carboxylic acid represented byheteroaryl--O--COOH wherein heteroaryl has the significance given above.The term "aminocarbonyl" alone or in combination, means anamino-substituted carbonyl (carbamoyl) group wherein the amino group canbe a primary; secondary or tertiary amino group containing substituentsselected from alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl radicalsand the like. The term "aminoalkanoyl" means an acyl group derived froman amino-substituted alkanecarboxylic acid wherein the amino group canbe a primary, secondary or tertiary amino group containing substituentsselected from alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl radicalsand the like. The term "halogen" means fluorine, chlorine, bromine oriodine. The term "haloalkyll" means an alkyl radical having thesignificance as defined above wherein one or more hydrogens are replacedwith a halogen. Examples of such haloalkyl radicals includechloromethyl, 1-bromoethyl, fluoromethyl, difluoromethyl,trifluoromethyl, 1,1,1-trifluoroethyl and the like. The term "leavinggroup" generally refers to groups readily displaceable by a nucleophile,such as an amine, a thiol or an alcohol nucleophile. Such leaving groupsare well known in the art. Examples of such leaving groups include, butare not limited to, N-hydroxysuccinimide, N-hydroxybenzotriazole,halides, triflates, tosylates and the like. Preferred leaving groups areindicated herein where appropriate. The term "amino acid side chain"means the side chain group, including the stereochemistry of the carbonto which it is attached, attached to the naturally occurring amino acidwhich distinguishes the amino acid from glycine. For example, the aminoacid side chain of alanine is methyl, of histidine is imidazolylmethyland phenylalanine is benzyl, and the attachment of such side chains tothe compound of this invention retain the naturally occurringstereochemistry of the carbon to which it is attached. The followingexample illustrates the definitions: ##STR5##

Procedures for preparing the compounds of Formula I are set forth below.It should be noted that the general procedure is shown as it relates topreparation of compounds having the specified stereochemistry, forexample, wherein the absolute stereochemistry about the hydroxyl groupis designated as (R). However, such procedures are generally applicableto those compounds of opposite configuration, e.g., where thestereochemistry about the hydroxyl group is (S). In addition, thecompounds having the (R) stereochemistry can be utilized to producethose having the (S) stereochemistry. For example, a compound having the(R) stereochemistry can be inverted to the (S) stereochemistry usingwell-known methods.

Preparation of Compounds of Formula I

The compounds of the present invention represented by Formula I abovecan be prepared utilizing the following general procedure. Thisprocedure is schematically shown in the following Schemes I and II:##STR6## a) amine b) sulfonyl chloride R⁴ SO₂ Cl (or anhydride)+acidscavenger c) deprotection d) coupling e) coupling. ##STR7## a) amine b)sulfonyl chloride R⁴ SO₂ Cl (or anhydride)+acid scavenger c)deprotection d) coupling e) coupling.

An N-protected chloroketone derivative of an amino acid having theformula: ##STR8## wherein P represents an amino protecting group, and R²is as defined above, is reduced to the corresponding alcohol utilizingan appropriate reducing agent. Suitable amino protecting groups are wellknown in the art and include carbobenzoxy, t-butoxycarbonyl, and thelike. A preferred amino protecting group is carbobenzoxy. A preferredN-protected chloroketone is N-benzyloxycarbonyl-L-phenylalaninechloromethyl ketone. A preferred reducing agent is sodium borohydride.The reduction reaction is conducted at a temperature of from -10° C. toabout 25° C., preferably at about 0° C., in a suitable solvent systemsuch as, for example, tetrahydrofuran, and the like. The N-protectedchloroketones are commercially available, e.g., such as from Bachem,Inc., Torrance, Calif. Alternatively, the chloroketones can be preparedby the procedure set forth in S. J. Fittkau, J. Prakt. Chem., 315, 1037(1973), and subsequently N-protected utilizing procedures which are wellknown in the art.

The halo alcohol can be utilized directly, as described below, or,preferably, is then reacted, preferably at room temperature, with asuitable base in a suitable solvent system to produce an N-protectedamino epoxide of the formula: ##STR9## wherein P and R² are as definedabove. Suitable solvent systems for preparing the amino epoxide includeethanol, methanol, isopropanol, tetrahydrofuran, dioxane, and the likeincluding mixtures thereof. Suitable bases for producing the epoxidefrom the reduced chloroketone include potassium hydroxide, sodiumhydroxide, potassium t-butoxide, DBU and the like. A preferred base ispotassium hydroxide.

Alternatively, a protected amino epoxide can be prepared, such as inco-owned and co-pending PCT patent application Ser. No. PCT/US93/04804which is incorporated herein by reference, starting with an L-amino acidwhich is reacted with a suitable amino-protecting group in a suitablesolvent to produce an amino-protected L-amino acid ester of the formula:##STR10## wherein P³ represents carboxyl-protecting group, e.g., methyl,ethyl, benzyl, tertiary-butyl and the like; R² is as defined above; andP¹ and P² independently are selected from amine protecting groups,including but not limited to, arylalkyl, substituted arylalkyl,cycloalkenylalkyl and substituted cycloalkenylalkyl, allyl, substitutedallyl, acyl, alkoxycarbonyl, aralkoxycarbonyl and silyl. Examples ofarylalkyl include, but are not limited to benzyl, ortho-methylbenzyl,trityl and benzhydryl, which can be optionally substituted with halogen,alkyl of C₁ -C₈, alkoxy, hydroxy, nitro, alkylene, amino, alkylamino,acylamino and acyl, or their salts, such as phosphonium and ammoniumsalts. Examples of aryl groups include phenyl, naphthalenyl, indanyl,anthracenyl, durenyl, 9-(9-phenylfluorenyl) and phenanthrenyl,cycloalkenylalkyl or substituted cycloalkylenylalkyl radicals containingcycloalkyls of C₆ -C₁₀ . Suitable acyl groups include carbobenzoxy,t-butoxycarbonyl, iso-butoxycarbonyl, benzoyl, substituted benzoyl,butyryl, acetyl, tri-fluoroacetyl, tri-chloroacetyl, phthaloyl and thelike.

Additionally, the P¹ and/or p² protecting groups can form a heterocyclicring with the nitrogen to which they are attached, for example,1,2-bis(methylene)benzene, phthalimidyl, succinimidyl, maleimidyl andthe like and where these heterocyclic groups can further includeadjoining aryl and cycloalkyl rings. In addition, the heterocyclicgroups can be mono-, di- or tri-substituted, e.g., nitrophthalimidyl.The term silyl refers to a silicon atom optionally substituted by one ormore alkyl, aryl and aralkyl groups.

Suitable silyl protecting groups include, but are not limited to,trimethylsilyl, triethylsilyl, tri-isopropylsilyl,tert-butyldimethylsilyl, dimethylphenylsilyl,1,2-bis(dimethylsilyl)benzene, 1,2-bis(dimethylsilyl)ethane anddiphenylmethylsilyl. Silylation of the amine functions to provide mono-or bis-disilylamine can provide derivatives of the aminoalcohol, aminoacid, amino acid esters and amino acid amide. In the case of aminoacids, amino acid esters and amino acid amides, reduction of thecarbonyl function provides the required mono- or bis-silyl aminoalcohol.Silylation of the aminoalcohol can lead to the N,N,O--tri-silylderivative. Removal of the silyl function from the silyl ether functionis readily accomplished by treatment with, for example, a metalhydroxide or ammonium flouride reagent, either as a discrete reactionstep or in situ during the preparation of the amino aldehyde reagent.Suitable silylating agents are, for example, trimethylsilyl chloride,tert-butydimethylsilyl chloride, phenyldimethylsilyl chlorie,diphenylmethylsilyl chloride or their combination products withimidazole or DMF. Methods for silylation of amines and removal of silylprotecting groups are well known to those skilled in the art. Methods ofpreparation of these amine derivatives from corresponding amino acids,amino acid amides or amino acid esters are also well known to thoseskilled in the art of organic chemistry including amino acid/amino acidester or aminoalcohol chemistry.

Preferably P¹ and P² are independently selected from aralkyl andsubstituted aralkyl. More preferably, each of P¹ and P² is benzyl.

The amino-protected L-amino acid ester is then reduced, to thecorresponding alcohol. For example, the amino-protected L-amino acidester can be reduced with diisobutylaluminum hydride at -78° C. in asuitable solvent such as toluene. Preferred reducing agents includelithium aluminium hydride, lithium borohydride, sodium borohydride,borane, lithium tri-ter-butoxyaluminum hydride, borane/THF complex. Mostpreferably, the reducing agent is diisobutylaluminum hydride (DiBAL-H)in toluene. The resulting alcohol is then converted, for example, by wayof a Swern oxidation, to the corresponding aldehyde of the formula:##STR11## wherein p¹, P² and R² are as defined above. Thus, adichloromethane solution of the alcohol is added to a cooled (-75 to-68° C.) solution of oxalyl chloride in dichloromethane and DMSO indichloromethane and stirred for 35 minutes.

Acceptable oxidizing reagents include, for example, sulfurtrioxide-pyridine complex and DMSO, oxalyl chloride and DMSO, acetylchloride or anhydride and DMSO, trifluoroacetyl chloride or anhydrideand DMSO, methanesulfonyl chloride and DMSO ortetrahydrothiaphene-S-oxide, toluenesulfonyl bromide and DMSO,trifluoromethanesulfonyl anhydride (triflic anhydride) and DMSO,phosphorus pentachloride and DMSO, dimethylphosphoryl chloride and DMSOand isobutylchloroformate and DMSO. The oxidation conditions reported byReetz et al [Angew Chem., 99, p. 1186, (1987)], Angew Chem. Int. Ed.Engl., 26, p. 1141, 1987) employed oxalyl chloride and DMSO at -78° C.

The preferred oxidation method described in this invention is sulfurtrioxide pyridine complex, triethylamine and DMSO at room temperature.This system provides excellent yields of the desired chiral protectedamino aldehyde usable without the need for purification i.e., the needto purify kilograms of intermediates by chromatography is eliminated andlarge scale operations are made less hazardous. Reaction at roomtemperature also eliminated the need for the use of low temperaturereactor which makes the process more suitable for commercial production.

The reaction may be carried out under and inert atmosphere such asnitrogen or argon, or normal or dry air, under atmospheric pressure orin a sealed reaction vessel under positive pressure. Preferred is anitrogen atmosphere. Alternative amine bases include, for example,tri-butyl amine, tri-isopropyl amine, N-methylpiperidine, N-methylmorpholine, azabicyclononane, diisopropylethylamine,2,2,6,6-tetramethylpiperidine, N,N-dimethylaminopyridine, or mixtures ofthese bases. Triethylamine is a preferred base. Alternatives to pureDMSO as solvent include mixtures of DMSO with non-protic or halogenatedsolvents such as tetrahydrofuran, ethyl acetate, toluene, xylene,dichloromethane, ethylene dichloride and the like. Dipolar aproticco-solvents include acetonitrile, dimethylformamide, dimethylacetamide,acetamide, tetramethyl urea and its cyclic analog, N-methylpyrrolidone,sulfolane and the like. Rather than N,N-dibenzylphenylalaninol as thealdehyde precursor, the phenylalaninol derivatives discussed above canbe used to provide the corresponding N-monosubstituted [either P¹ or P²=H] or N,N-disubstituted aldehyde.

In addition, hydride reduction of an amide or ester derivative of thecorresponding alkyl, benzyl or cycloalkenyl nitrogen protectedphenylalanine, substituted phenylalanine or cycloalkyl analog ofphenyalanine derivative can be carried out to provide the aldehydes.Hydride transfer is an additional method of aldehyde synthesis underconditions where aldehyde condensations are avoided, cf, OppenauerOxidation.

The aldehydes of this process can also be prepared by methods ofreducing protected phenylalanine and phenylalanine analogs or theiramide or ester derivatives by, e.g., sodium amalgam with HCl in ethanolor lithium or sodium or potassium or calcium in ammonia. The reactiontemperature may be from about -20° C. to about 45° C., and preferablyfrom abut 5° C. to about 25° C. Two additional methods of obtaining thenitrogen protected aldehyde include oxidation of the correspondingalcohol with bleach in the presence of a catalytic amount of2,2,6,6-tetramethyl-1-pyridyloxy free radical. In a second method,oxidation of the alcohol to the aldehyde is accomplished by a catalyticamount of tetrapropylammonium perruthenate in the presence ofN-methylmorpholine-N-oxide.

Alternatively, an acid chloride derivative of a protected phenylalanineor phenylalanine derivative as disclosed above can be reduced withhydrogen and a catalyst such as Pd on barium carbonate or bariumsulphate, with or without an additional catalyst moderating agent suchas sulfur or a thiol (Rosenmund Reduction).

The aldehyde resulting from the Swern oxidation is then reacted with ahalomethyllithium reagent, which reagent is generated in situ byreacting an alkyllithium or arylithium compound with a dihalomethanerepresented by the formula X¹ CH₂ X² wherein X¹ and X² independentlyrepresent I, Br or Cl. For example, a solution of the aldehyde andchloroiodomethane in THF is cooled to -78° C. and a solution ofn-butyllithium in hexane is added. The resulting product is a mixture ofdiastereomers of the corresponding amino-protected epoxides of theformulas: ##STR12## The diastereomers can be separated e.g., bychromatography, or, alternatively, once reacted in subsequent steps thediastereomeric products can be separated. For compounds having the (S)stereochemistry, a D-amino acid can be utilized in place of the L-aminoacid.

The addition of chloromethylithium or bromomethylithium to a chiralamino aldehyde is highly diastereoselective. Preferably, thechloromethyllithium or bromomethylithium is generated in-situ from thereaction of the dihalomethane and n-butyllithium. Acceptablemethyleneating halomethanes include chloroiodomethane,bromochloromethane, dibromomethane, diiodomethane, bromofluoromethaneand the like. The sulfonate ester of the addition product of, forexample, hydrogen bromide to formaldehyde is also a methyleneatingagent. Tetrahydrofuran is the preferred solvent, however alternativesolvents such as toluene, dimethoxyethane, ethylene dichloride,methylene chloride can be used as pure solvents or as a mixture. Dipolaraprotic solvents such as acetonitrile, DMF, N-methylpyrrolidone areuseful as solvents or as part of a solvent mixture. The reaction can becarried out under an inert atmosphere such as nitrogen or argon. Forn-butyl lithium can be substituted other organometalic reagents reagentssuch as methyllithium, tert-butyl lithium, sec-butyl lithium,phenyllithium, phenyl sodium and the like. The reaction can be carriedout at temperatures of between about -80° C. to 0° C. but preferablybetween about -80° C. to -20° C. The most preferred reactiontemperatures are between -40° C. to -15° C. Reagents can be added singlybut multiple additions are preferred in certain conditions. Thepreferred pressure of the reaction is atmospheric however a positivepressure is valuable under certain conditions such as a high humidityenvironment.

Alternative methods of conversion to the epoxides of this inventioninclude substitution of other charged methylenation precurser speciesfollowed by their treatment with base to form the analogous anion.Examples of these species include trimethylsulfoxonium tosylate ortriflate, tetramethylammonium halide, methyldiphenylsulfoxonium halidewherein halide is chloride, bromide or iodide.

The conversion of the aldehydes of this invention into their epoxidederivative can also be carried out in multiple steps. For example, theaddition of the anion of thioanisole prepared from, for example, a butylor aryl lithium reagent, to the protected aminoaldehyde, oxidation ofthe resulting protected aminosulfide alcohol with well known oxidizingagents such as hydrogen peroxide, tert-butyl hypochlorite, bleach orsodium periodate to give a sulfoxide. Alkylation of the sulfoxide with,for example, methyl iodide or bromide, methyl tosylate, methyl mesylate,methyl triflate, ethyl bromide, isopropyl bromide, benzyl chloride orthe like, in the presence of an organic or inorganic base Alternatively,the protected aminosulfide alcohol can be alkylated with, for example,the alkylating agents above, to provide a sulfonium salts that aresubsequently converted into the subject epoxides with tert-amine ormineral bases.

The desired epoxides formed, using most preferred conditions,diastereoselectively in ratio amounts of at least about an 85:15 ratio(S:R). The product can be purified by chromatography to give thediastereomerically and enantiomerically pure product but it is moreconveniently used directly without purification to prepare retroviralprotease inhibitors. The foregoing process is applicable to mixtures ofoptical isomers as well as resolved compounds. If a particular opticalisomer is desired, it can be selected by the choice of startingmaterial, e.g., L-phenylalanine, D-phenylalanine, L-phenylalaninol,D-phenylalaninol, D-hexahydrophenylalaninol and the like, or resolutioncan occur at intermediate or final steps. Chiral auxiliaries such as oneor two equivilants of camphor sulfonic acid, citric acid, camphoricacid, 2-methoxyphenylacetic acid and the like can be used to form salts,esters or amides of the compounds of this invention. These compounds orderivatives can be crystallized or separated chromatographically usingeither a chiral or achiral column as is well known to those skilled inthe art.

The amino epoxide is then reacted, in a suitable solvent system, with anequal amount, or preferably an excess of, a desired amine of theformula:

    R.sup.3 NH.sub.2

wherein R³ is hydrogen or is as defined above. The reaction can beconducted over a wide range of temperatures, e.g., from about 10° C. toabout 100° C., but is preferably, but not necessarily, conducted at atemperature at which the solvent begins to reflux. Suitable solventsystems include protic, non-protic and dipolar aprotic organic solventssuch as, for example, those wherein the solvent is an alcohol, such asmethanol, ethanol, isopropanol, and the like; ethers such astetrahydrofuran, dioxane and the like, and toluene,N,N-dimethylformamide, dimethyl sulfoxide, and mixtures thereof. Apreferred solvent is isopropanol. Exemplary amines corresponding to theformula R³ NH₂ include benzyl amine, isobutylamine, n-butyl amine,isopentyl amine, isoamylamine, cyclohexanemethyl amine, naphthylenemethyl amine and the like. The resulting product is a 3-(N-protectedamino)-3-(R²)-1-(NHR³)-propan-2-ol derivative (hereinafter referred toas an amino alcohol) can be represented by the formulas: ##STR13##wherein P, P¹, P², R² and R³ are as described above. Alternatively, ahaloalcohol can be utilized in place of the amino epoxide.

The amino alcohol defined above is then reacted in a suitable solventwith a sulfonyl chloride (R⁴ SO₂ Cl) or sulfonyl anhydride in thepresence of an acid scavenger. Suitable solvents in which the reactioncan be conducted include methylene chloride, tetrahydrofuran. Suitableacid scavengers include triethylamine, pyridine. Preferred sulfonylchlorides are methanesulfonyl chloride and benzenesulfonyl chloride. Theresulting sulfonamide derivative can be represented, depending on theepoxide utilized by the formulas ##STR14## wherein P, P¹, P² ; R², R³and R⁴ are as defined above. These intermediates are useful forpreparing inhibitor compounds of the present invention and are alsoactive inhibitors of retroviral proteases.

The sulfonyl halides of the formula R⁴ SO₂ X can be prepared by thereaction of a suitable Grignard or alkyl lithium reagent with sulfurylchloride, or sulfur dioxide followed by oxidation with a halogen,preferably chlorine. Also, thiols may be oxidized to sulfonyl chloridesusing chlorine in the presence of water under carefully controlledconditions. Additionally, sulfonic acids may be converted to sulfonylhalides using reagents such as PCl₅, and also to anhydrides usingsuitable dehydrating reagents. The sulfonic acids may in turn beprepared using procedures well known in the art. Such sulfonic acids arealso commercially available. In place of the sulfonyl halides, sulfinylhalides (R⁴ SOX) or sulfenyl halides (R⁴ SX) can be utilized to preparecompounds wherein the --SO₂ -- moiety is replaced by an --SO-- or --S--moiety, respectively.

Following preparation of the sulfonamide derivative, the aminoprotecting group P or P¹ and P² amino protecting groups are removedunder conditions which will not affect the remaining portion of themolecule. These methods are well known in the art and include acidhydrolysis, hydrogenolysis and the like. A preferred method involvesremoval of the protecting group, e.g., removal of a carbobenzoxy group,by hydrogenolysis utilizing palladium on carbon in a suitable solventsystem such as an alcohol, acetic acid, and the like or mixturesthereof. Where the protecting group is a t-butoxycarbonyl group, it canbe removed utilizing an inorganic or organic acid, e.g., HCl ortrifluoroacetic acid, in a suitable solvent system, e.g., dioxane ormethylene chloride. The resulting product is the amine salt derivative.Following neutralization of the salt, the amine is then reacted with anamino acid or corresponding derivative thereof represented by theformula (PN[CR¹ 'R¹ "]_(t) CH(R¹)COOH) wherein t, R¹, R¹ ' and R¹ " areas defined above, to produce the antiviral compounds of the presentinvention having the formula: ##STR15## wherein t, P, R¹, R¹ ', R¹ ",R², R³ and R⁴ are as defined above. Preferred protecting groups in thisinstance are a benzyloxycarbonyl group or a t-butoxycarbonyl group.Where t is O and R¹ is alkyl, alkenyl, alkynyl, cycloalkyl, --CH₂ SO₂NH₂, --CH₂ CO₂ CH₃, --CO₂ CH₃, --CONH₂, --CH₂ C(O)NHCH₃, --C(CH₃)₂ (SH),--C(CH₃)₂ (SCH₃), --C(CH₃)₂ [S(O)CH₃ ], --C(CH₃)₂ [S(O₂)CH₃ ], or anamino acid side chain, such materials are well known and many arecommercially available from Sigma-Aldrich.

Where the amine is reacted with a derivative of an amino acid, e.g.,when t=1, so that the amino acid is a β-amino acid, such β-amino acidscan be prepared according to the procedure set forth in a co-owned,copending patent application, U.S. Ser. No. 07/853,561 or the followingprocedures

Various methods have been proposed for the preparation of chiral β-aminoacids. See, for example, Chemistry and Biochemistry of Amino Acids, Vol.4, Chapter 5, pp. 250-57, B. Weinstein, Ed., Dekker, N.Y. (1975).Furukawa et al, Chem. Pharm. Bull., 25, 1319 (1977), disclose asymmetricsynthesis of β-amino acids by addition of chiral amines to carbon-carbondouble bonds having nitrile or ester groups in the α-position. However,optical purities of the β-amino acids thus produced range from 2 to 19%.Furukawa et al also report that optically active β-amino acids have beenproduced with optical purities ranging from 2 to 28% by reacting chiralSchiff bases with Reformsky reagent. Terentev et al, Dohl. Ahad. NauhSSR, 163,674 (1965) disclose synthesis of β-aminobutyric acids involvingaddition of chiral amines to crotonic acid with optical purities rangingfrom 7-9%.

Brown et al, Tetrahedron Lett., Vol. 28, No. 19, pp 2179-2182 (1987),disclose a method of preparing optically active disubstituted β-aminoacids which involves asymmetric catalytic hydrogenation of N-substitutedα-(aminoalkyl) acrylates. In order to verify the stereochemistry of theproduct, Curtius rearrangement was effected on the monomethyl ester ofoptically enriched RR-anti-2,3-dimethyl-succinic acid and trapping ofthe incipient isocyanate derivative with tertiary alcohol, namely,t-butyl alcohol, to give the corresponding R-enriched β-amino acid.

Ninomita et al, Tetrahedron Lett., Vol. 30, 2152-2157 (1975) studied theCurtius rearrangement utilizing benzoic acid, diphenylphosphoryl azideand triethylamine followed by treatment with various alcohols and foundthat t-butyl alcohol gives yields superior to benzyl alcohol, ethanoland phenol.

Utilization of a primary or secondary alcohol to trap an isocyanatederivative of a chiral mono-substituted succinate, and, in particular,in a Curtius rearrangement of a chiral mono-substituted succinate, toproduce chiral β-amino acids significantly increases the overall yield.The resulting carbamate-protected β-amino esters are then saponified toproduce the corresponding carbamate-protected β-amino acids which arethen deprotected to produce β-amino acids possessing the same absoluteconfiguration as naturally-occurring (L)-amino acids.

The overall reaction sequence can be shown as follows: ##STR16## whereinR¹, R¹ ', R¹ ", and P³ are as defined above and P⁴ OH are preferablyrepresents radicals derived from primary and secondary alcohols.

This process can also be used in the asymetric synthesis of β-aminoacids represented by the formula: ##STR17## wherein R¹, R¹ ' and R¹ "are as defined above. Such compounds are formed by Curtius rearrangementof 2(R)-substituted succinates represented by the formula ##STR18##wherein R¹, R¹ ', R¹ " and P³ are as defined above, to afford theisocyanate derivative: ##STR19## Using 2(S)-substituted succinates,2(S)-substituted β-amino acids can also be prepared stereospecifically.

Curtius rearrangement involves pyrolysis of acyol azides ##STR20## toyield isocyanates (R--N═C═O) which can be subsequently hydrolyzed togive amines. See March, Advanced Organic Chemistry, p. 1005, 2nd ed(1977). As a general rule, Curtius rearrangement is a concerted reactionand therefore proceeds with retention of configuration of the startingmaterials. Determination of specific reaction conditions for effectingCurtius rearrangements of various succinates is within the skill of onein the art familiar with such reactions. In the method of the presentinvention, Curtius rearrangement to afford the desired isocyante ispreferably effected by treating a 2-substituted succinate with oneequivalent of diphenoxyphosphoryl azide (PhO)₂ PON₃ and triethylamine toform the acyl azide followed by heating in an inert solvent, such as inwarm toluene, preferably at about 80° C. for about three hours, toafford the isocyante derivative.

Suitable primary and secondary alcohols include those represented by theformula P⁴ OH where P⁴ representes substituted and unsubstituted alkyl,cycloalkyl, aralkyl and aryl radicals, as well as suitable equivalentssuch as, for example, silyl radicals. Preferably, the primary andsecondary alcohols are those wherein P⁴ represents substituted andunsubstituted, straight chain as well as branched chain, alkyl radicalshaving from 1 to about 12 carbon atoms, substituted and unsubstitutedcycloalkyl radicals having from 4 to about 7 carbon atoms, andsubstituted and unsubstituted aryl, alkaryl and aralkyl radicals.Examples of such suitable alcohols include benzyl alcohol, isopropylalcohol, 4-methoxybenzyl alcohol, 2-trimethylsilylethanol, fluorenylmethanol and benzhydrol. Preferred alcohols are benzyl alcohol and4-methoxybenzyl alcohol. Other primary and secondary alcohols suitablefor use in the practice of the present invention will be readilyapparent to those skilled in the art.

The ester derivative is then saponified by any one of numerouswell-known procedures, such as by treatment with aqueous lithiumhydroxide/THF (tetrahydrofuran), preferably for three hours at 0° C. Theresultant product is the corresponding carbamate-protected β-aminoacids. These are subsequently deprotected by any one of severalwell-known procedures, such as by acid catalyzed hydrolysis or byhydrogenolysis, to produce the corresponding deprotected β-amino acids.Alternatively, the carbamate-protected β-amino acid can be coupled tothe amine ##STR21## followed by deprotection and incorporation of R andR'.

The N-protecting group can be subsequently removed, if desired,utilizing the procedures described above, and then reacted with acarboxylate represented by the formula: ##STR22## wherein R is asdefined above and L is an appropriate leaving group such as a halide.Preferably, where R¹ is a side chain of a naturally occurring α-aminoacid, R is a 2-quinoline carbonyl group derived fromN-hydroxysuccinimide-2-quinoline carboxylate, i.e., L is hydroxysuccinimide. A solution of the free amine (or amine acetate salt) andabout 1.0 equivalent of the carboxylate are mixed in an appropriatesolvent system and optionally treated with up to five equivalents of abase such as, for example, N-methylmorpholine, at about roomtemperature. Appropriate solvent systems include tetrahydrofuran,methylene chloride or N,N-dimethylformamide, and the like, includingmixtures thereof.

Alternatively, the protected amino alcohol from the epoxide opening canbe further protected at the newly introduced amino group with aprotecting group P' which is not removed when the first protecting P isremoved. One skilled in the art can choose appropriate combinations of Pand P'. One suitable choice is when P is Cbz and P' is Boc. Theresulting compound represented by the formula: ##STR23## can be carriedthrough the remainder of the synthesis to provide a compound of theformula: ##STR24## and the new protecting group P' is selectivelyremoved, and following deprotection, the resulting amine reacted to formthe sulfonamide derivative as described above. This selectivedeprotection and conversion to the sulfonamide can be accomplished ateither the end of the synthesis or at any appropriate intermediate stepif desired.

The thiocarbonyl compounds of this invention are really prepared bymethods well known to those skilled in the art, for example, bytreatment of a carbonyl compound with Lawesson's reagent(2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide)which is an article of commerce. Phosphoruspentasulfide may also be usedor one can treat an amine of this invention with a pre-formedthiocarbonyl reagent such as thiocarbonylchlorid in the presence ofbase.

In place of the sulfonyl halides, sulfinyl halides (RSOCl) and sulfenylhalides (RSCl) can be utilized to prepare compounds wherein the --SO₂ --moiey is replaced by --SO-- or --S--, respectively.

It is contemplated that for preparing compounds of the Formulas havingR⁶, the compounds can be prepared following the procedure set forthabove and, prior to coupling the sulfonamide derivative or analogthereof, e.g. coupling to the amino acid PNH(CH₂)_(t) CH(R¹)COOH,carried through a procedure referred to in the art as reductiveamination. Thus, a sodium cyanoborohydride and an appropriate aldehydeor ketone can be reacted with the sulfonamide derivative compound orappropriate analog at room temperature in order to reductively aminateany of the compounds of Formulas I-IV. It is also contemplated thatwhere R³ of the amino alcohol intermediate is hydrogen, the inhibitorcompounds of the present invention wherein R³ is alkyl, or othersubstituents wherein the α-C contains at least one hydrogen, can beprepared through reductive amination of the final product of thereaction between the amino alcohol and the amine or at any other stageof the synthesis for preparing the inhibitor compounds.

Contemplated equivalents of the general formulas set forth above for theantiviral compounds and derivatives as well as the intermediates arecompounds otherwise corresponding thereto and having the same generalproperties, such as tautomers thereof as well as compounds, wherein oneor more of the various R groups are simple variations of thesubstituents as defined therein, e.g., wherein R is a higher alkyl groupthan that indicated. In addition, where a substituent is designated as,or can be, a hydrogen, the exact chemical nature of a substituent whichis other than hydrogen at that position, e.g., a hydrocarbyl radical ora halogen, hydroxy, amino and the like functional group, is not criticalso long as it does not adversely affect the overall activity and/orsynthesis procedure.

The chemical reactions described above are generally disclosed in termsof their broadest application to the preparation of the compounds ofthis invention. Occasionally, the reactions may not be applicable asdescribed to each compound included within the disclosed scope. Thecompounds for which this occurs will be readily recognized by thoseskilled in the art. In all such cases, either the reactions can besuccessfully performed by conventional modifications known to thoseskilled in the art, e.g., by appropriate protection of interferinggroups, by changing to alternative conventional reagents, by routinemodification of reaction conditions, and the like, or other reactionsdisclosed herein or otherwise conventional, will be applicable to thepreparation of the corresponding compounds of this invention. In allpreparative methods, all starting materials are known or readilypreparable from known starting materials.

Without further elaboration, it is believed that one skilled in the artcan, using the preceding description, utilize the present invention toits fullest extent. The following preferred specific embodiments are,therefore, to be construed as merely illustrative, and not limitative ofthe remainder of the disclosure in any way whatsoever.

All reagents were used as received without purification. All proton andcarbon NMR spectra were obtained on either a Varian VXR-300 or VXR-400nuclear magnetic resonance spectrometer.

The following Examples 1 through 9 illustrate preparation ofintermediates. These intermediates are useful in preparing the inhibitorcompounds of the present invention as illustrated in Examples 10-16. Inaddition, the intermediates of Examples 2-6 are also retroviral proteaseinhibitors and inhibit, in particular, HIV protease.

EXAMPLE 1A ##STR25## Preparation ofN[3(S)-benzyloxycarbonylamino-2(R)-hydroxy-4-phenylbutyl]-N-isoamylamine

Part A:

To a solution of 75.0 g (0.226 mol) ofN-benzyloxycarbonyl-L-phenylalanine chloromethyl ketone in a mixture of807 mL of methanol and 807 mL of tetrahydrofuran at -2° C., was added13.17 g (0.348 mol, 1.54 equiv.) of solid sodium borohydride over onehundred minutes. The solvents were removed under reduced pressure at 40°C. and the residue dissolved in ethyl acetate (approx. 1 L). Thesolution was washed sequentially with 1M potassium hydrogen sulfate,saturated sodium bicarbonate and then saturated sodium chloridesolutions. After drying over anhydrous magnesium sulfate and filtering,the solution was removed under reduced pressure. To the resulting oilwas added hexane (approx. 1 L) and the mixture warmed to 60° C. withswirling. After cooling to room temperature, the solids were collectedand washed with 2 L of hexane. The resulting solid was recrystallizedfrom hot ethyl acetate and hexane to afford 32.3 g (43% yield) ofN-benzyloxycarbonyl-3(S)-amino-1-chloro-4-phenyl-2(S)-butanol, mp150-151° C. and M+Li⁺ =340.

Part B:

To a solution of 6.52 g (0.116 mol, 1.2 equiv.) of potassium hydroxidein 968 mL of absolute ethanol at room temperature, was added 32.3 g(0.097 mol) of N-CBZ-3(S)-amino-1-chloro-4-phenyl-2(S)-butanol. Afterstirring for fifteen minutes, the solvent was removed under reducedpressure and the solids dissolved in methylene chloride. After washingwith water, drying over magnesium sulfate, filtering and stripping, oneobtains 27.9 g of a white solid. Recrystallization from hot ethylacetate and hexane afforded 22.3 g (77% yield) ofN-benzyloxycarbonyl-3(S)-amino-1,2(S)-epoxy-4-phenylbutane, mp 102-103°C. and MH⁺ 298.

Part C:

A solution of N-benzyloxycarbonyl3(S)-amino-1,2-(S)-epoxy-4-phenylbutane (1.00 g, 3.36 mmol) andisoamylamine (4.90 g, 67.2 mmol, 20 equiv.) in 10 mL of isopropylalcohol was heated to reflux for 1.5 hours. The solution was cooled toroom temperature, concentrated in vacuo and then poured into 100 mL ofstirring hexane whereupon the product crystallized from solution. Theproduct was isolated by filtration and air dried to give 1.18 g, 95% ofN=[[3(S)-phenylmethylcarbamoyl)amino-2(R)-hydroxy-4-phenylbutyl]N-[(3-methylbutyl)]aminemp 108.0-109.5° C., MH⁺ m/z=371.

EXAMPLE 1B ##STR26## Preparation ofN,N-dibenzyl-3(S)-amino-1,2-(S)-epoxy-4-phenylbutane

Step A:

A solution of L-phenylalanine (50.0 g, 0.302 mol), sodium hydroxide(24.2 g, 0.605 mol) and potassium carbonate (83.6 g, 0.605 mol) in water(500 ml) was heated to 97° C. Benzyl bromide (108.5 ml, 0.912 mol) wasthen slowly added (addition time ˜25 min). The mixture was then stirredat 97° C. for 30 minutes. The solution was cooled to room temperatureand extracted with toluene (2×250 ml). The combined organic layers werethen washed with water, brine, dried over magnesium sulfate, filteredand concentrated to give an oil product. The crude product was then usedin the next step without purification.

Step B:

The crude benzylated product of the above step was dissolved in toluene(750 ml) and cooled to -55° C. A 1.5M solution of DIBAL-H in toluene(443.9 ml, 0.666 mol) was then added at a rate to maintain thetemperature between -55° to -50° C. (addition time -1 hour). The mixturewas stirred for 20 minutes at -55° C. The reaction was quenched at -55°C. by the slow addition of methanol (37 ml). The cold solution was thenpoured into cold (5° C.) 1.5 N HCl solution (1.8 L). The precipitatedsolid (approx. 138 g) was filtered off and washed with toluene. Thesolid material was suspended in a mixture of toluene (400 ml) and water(100 ml) The mixture was cooled to 5° C., treated with 2.5 N NaOH (186ml) and then stirred at room temperature until the solid was dissolved.The toluene layer was separated from the aqueous phase and washed withwater and brine, dried over magnesium sulfate, filtered and concentratedto a volume of 75 ml (89 g). Ethyl acetate (25 ml) and hexane (25 ml)were then added to the residue upon which the alcohol product began tocrystallize. After 30 min., an additional 50 ml hexane was added topromote further crystallization. The solid was filtered off and washedwith 50 ml hexane to give approximately 35 g of material. A second cropof material could be isolated by refiltering the mother liquor Thesolids were combined and recrystallized from ethyl acetate (20 ml) andhexane (30 ml) to give, in 2 crops, approximately 40 g (40% fromL-phenylalanine) of analytically pure alcohol product. The motherliquors were combined and concentrated (34 g). The residue was treatedwith ethyl acetate and hexane which provided an additional 7 g (˜7%yield) of slightly impure solid product. Further optimization in therecovery from the mother liquor is probable.

Alternatively, the alcohol was prepared from L-phenylalaninol.L-phenylalaninol (176.6 g, 1.168 mol) was added to a stirred solution ofpotassium carbonate (484.6 g, 3.506 mol) in 710 mL of water. The mixturewas heated to 65° C. under a nitrogen atmosphere. A solution of benzylbromide (400 g, 2.339 mol) in 3A ethanol (305 mL) was added at a ratethat maintained the temperature between 60-68° C. The biphasic solutionwas stirred at 65° C. for 55 min and then allowed to cool to 10° C. withvigorous stirring. The oily product solidified into small granules. Theproduct was diluted with 2.0 L of tap water and stirred for 5 minutes todissolve the inorganic by products. The product was isolated byfiltration under reduced pressure and washed with water until the pH is7. The crude product obtained was air dried overnite to give a semi-drysolid (407 g) which was recrystallized from 1.1 L of ethylacetate/heptane (1:10 by volume). The product was isolated by filtration(at -8° C.), washed with 1.6 L of cold (-10° C.) ethyl acetate/heptane(1:10 by volume) and air-dried to give 339 g (88% yield) ofβS-2-[Bis(phenylmethyl)amino]benzene-propanol, mp 71.5-73.0° C. Moreproduct can be obtained from the mother liquor if necessary. The otheranalytical characterization was identical to compound prepared asdescribed above.

Step C:

A solution of oxalyl chloride (8.4 ml, 0.096 mol) in dichloromethane(240 ml) was cooled to -74° C. A solution of DMSO (12.0 ml, 0.155 mol)in dichloromethane (50 ml) was then slowly added at a rate to maintainthe temperature at -74° C. (addition time ˜1.25 hr). The mixture wasstirred for 5 min. followed by addition of a solution of the alcohol(0.074 mol) in 100 ml of dichloromethane (addition time -20 min., temp.-75° C. to -68° C.). The solution was stirred at -78° C. for 35 minutes.Triethylamine (41.2 ml, 0.295 mol) was then added over 10 min. (temp.-78° to -68° C.) upon which the ammonium salt precipitated. The coldmixture was stirred for 30 min. and then water (225 ml) was added. Thedichloromethane layer was separated from the aqueous phase and washedwith water, brine, dried over magnesium sulfate, filtered andconcentrated. The residue was diluted with ethyl acetate and hexane andthen filtered to further remove the ammonium salt. The filtrate wasconcentrated to give the desired aldehyde product. The aldehyde wascarried on to the next step without purification.

Temperatures higher than -70° C. have been reported in the literaturefor the Swern oxidation. Other Swern modifications and alternatives tothe Swern oxidations are also possible.

Alternatively, the aldehyde was prepared as follows. (200 g, 0.604 mol)was dissolved in triethylamine (300 mL, 2.15 mol). The mixture wascooled to 12° C. and a solution of sulfur trioxide/pyridine complex (380g, 2.39 mol) in DMSO (1.6 L) was added at a rate to maintain thetemperature between 8-17° C. (addition time -1.0 h). The solution wasstirred at ambient temperature under a nitrogen atmosphere for 1.5 hourat which time the reaction was complete by TLC analysis (33% ethylacetate/hexane, silica gel). The reaction mixture was cooled with icewater and quenced with 1.6 L of cold water (10-15° C.) over 45 minutes.The resultant solution was extracted with ethyl acetate (2.0 L), washedwith 5% citric acid (2.0 L), and brine (2.2 L), dried over MgSO₄ (280 g)and filtered. The solvent was removed on a rotary evaporator at 35-40°C. and then dried under vaccuum to give 198.8 g ofαS-[Bis-(phenylmethyl)amino]-benzenepropanaldehyde as a pale yellow oil(99.9%). The crude product obtained was pure enough to be used directlyin the next step without purification. The analytical data of thecompound were consistent with the published literature. [α]_(D)25=-92.9° (c 1.87, CH₂ Cl₂); ¹ H NMR (400 MHz, CDCl₃) ∂, 2.94 and 3.15(ABX-System, 2H, J_(AB) =13.9 Hz, J_(AX) =7.3 Hz and J_(BX) =6.2 Hz),3.56 (t, 1H, 7.1 Hz), 3.69 and 3.82 (AB-System, 4H, J_(AB) =13.7 Hz),7.25 (m, 15 H) and 9.72 (s, 1H); HRMS calcd for (M+1) C₂₃ H₂₄ NO330.450, found: 330.1836. Anal. Calcd. for C₂₃ H₂₃ ON: C, 83.86; H,7.04; N, 4.25. Found: C, 83.64; H, 7.42; N, 4.19. HPLC on chiralstationary phase:(S,S) Pirkle-Whelk--O 1 column (250×4.6 mm I.D.),mobile phase: hexane/isopropanol (99.5:0.5, v/v), flow-rate: 1.5 ml/min,detection with UV detector at 210 nm. Retention time of the desiredS-isomer: 8.75 min., retention time of the R-enanatiomer 10.62 min.

Step D:

A solution of αS-[BiS(phenylmethyl)amino] benzene-propanaldehyde (191.7g, 0.58 mol) and chloroiodomethane (56.4 mL, 0.77 mol) intetrahydrofuran (1.8 L) was cooled to -30 to -35° C. (colder temperaturesuch as -70° C. also worked well but warmer temperatures are morereadily achieved in large scale operations) in a stainless steel reactorunder a nitrogen atmosphere. A solution of n-butyllithium in hexane (1.6M, 365 mL, 0.58 mol) was then added at a rate that maintained thetemperature below -25° C. After addition the mixture was stirred at -30to -35° C. for 10 minutes. More additions of reagents were carried outin the following manner: (1) additional chloroiodomethane (17 mL) wasadded, followed by n-butyllithium (110 mL) at <-25° C. After additionthe mixture was stirred at -30 to -35° C. for 10 minutes. This wasrepeated once. (2) Additional chloroiodomethane (8.5 mL, 0.11 mol) wasadded, followed by n-butyllithium (55 mL, 0.088 mol) at <-25° C. Afteraddition, the mixture was stirred at -30 to -35° C. for 10 minutes. Thiswas repeated 5 times. (3) Additional chloroiodomethane (8.5 mL, 0.11mol) was added, followed by n-butyllithium (37 mL, 0.059 mol) at <-25°C. After addition, the mixture was stirred at -30 to -35° C. for 10minutes. This was repeated once. The external cooling was stopped andthe mixture warmed to ambient temp. over 4 to 16 hours when TLC (silicagel, 20% ethyl acetate/hexane) indicated that the reaction wascompleted. The reaction mixture was cooled to 10° C. and quenched with1452 g of 16% ammonium chloride solution (prepared by dissolving 232 gof ammonium chloride in 1220 mL of water), keeping the temperature below23° C. The mixture was stirred for 10 minutes and the organic andaqueous layers were separated. The aqueous phase was extracted withethyl acetate (2×500 mL). The ethyl acetate layer was combined with thetetrahydrofuran layer. The combined solution was dried over magnesiumsulfate (220 g), filtered and concentrated on a rotary evaporator at 65°C. The brown oil residue was dried at 70° C. in vacuo (0.8 bar) for 1 hto give 222.8 g of crude material. (The crude product weight was >100%.Due to the relative instability of the product on silica gel, the crudeproduct is usually used directly in the next step without purification).The diastereomeric ratio of the crude mixture was determined by protonNMR: (2S)/(2R): 86:14. The minor and major epoxide diastereomers werecharacterized in this mixture by tlc analysis (silica gel, 10% ethylacetate/hexane), Rf=0.29 & 0.32, respectively. An analytical sample ofeach of the diastereomers was obtained by purification on silica-gelchromatography (3% ethyl acetate/hexane) and characterized as follows:

N,N,αS-Tris(phenylmethyl)-2S-oxiranemethanamine; ¹ H NMR (400 MHz,CDCl₃) ∂ 2.49 and 2.51 (AB-System, 1H, J_(AB) =2.82), 2.76 and 2.77(AB-System, 1H, J_(AB) =4.03), 2.83 (m, 2H), 2.99 & 3.03 (AB-System, 1H,J_(AB) =10.1 Hz), 3.15 (m, 1H), 3.73 & 3.84 (AB-System, 4H, J_(AB)=14.00), 7.21 (m, 15H); ¹³ C NMR (400 MHz,CDCl₃) ∂ 139.55, 129.45,128.42, 128.14, 128.09, 126.84, 125.97, 60.32, 54.23, 52.13, 45,99,33.76; HRMS calcd for C₂₄ H₂₆ NO (M+1) 344.477, found 344.2003.

N,N,αS-Tris(phenylmethyl)-2R-oxiranemethanamine; ¹ H NMR (300 MHz,CDCl₃) ∂ 2.20 (m, 1H), 2.59 (m, 1H), 2.75 (m, 2H), 2.97 (m, 1H), 3.14(m, 1H), 3.85 (AB-System, 4H), 7.25 (m, 15H).HPLC on chiral stationaryphase: Pirkle-Whelk--O 1 column (250×4.6 mm I.D.), mobile phase:hexane/isopropanol (99.5:0.5, v/v), flow-rate: 1.5 ml/min, detectionwith UV detector at 210 nm. Retention time of (8): 9.38 min., retentiontime of enanatiomer of (4): 13.75 min.

Alternatively, a solution of the crude aldehyde 0.074 mol andchloroiodomethane (7.0 ml, 0.096 mol) in tetrahydrofuran (285 ml) wascooled to -78° C., under a nitrogen atmosphere. A 1.6 M solution ofn-butyllithium in hexane (25 ml, 0.040 mol) was then added at a rate tomaintain the temperature at -75° C. (addition time -15 min.). After thefirst addition, additional chloroiodomethane (1.6 ml, 0.022 mol) wasadded again, followed by n-butyllithium (23 ml, 0.037 mol), keeping thetemperature at -75° C. The mixture was stirred for 15 min. Each of thereagents, chloroiodomethane (0.70 ml, 0.010 mol) and n-butyllithium (5ml, 0.008 mol) were added 4 more times over 45 min. at -75° C. Thecooling bath was then removed and the solution warmed to 22° C. over 1.5hr. The mixture was poured into 300 ml of saturated aq. ammoniumchloride solution. The tetrahydrofuran layer was separated. The aqueousphase was extracted with ethyl acetate (1×300 ml). The combined organiclayers were washed with brine, dried over magnesium sulfate, filteredand concentrated to give a brown oil (27.4 g). The product could be usedin the next step without purification. The desired diastereomer can bepurified by recrystallization at a subsequent step. The product couldalso be purified by chromatography.

Alternatively, a solution ofαS-[Bis(phenylmethyl)amino]benzene-propanaldehyde (178.84 g, 0.54 mol)and bromochloromethane (46 mL, 0.71 mol) in tetrahydrofuran (1.8 L) wascooled to -30 to -35° C. (colder temperature such as -70° C. also workedwell but warmer temperatures are more readily achieved in large scaleoperations) in a stainless steel reactor under a nitrogen atmosphere. Asolution of n-butyllithium in hexane (1.6 M, 340 mL, 0.54 mol) was thenadded at a rate that maintained the temperature below -25° C. Afteraddition the mixture was stirred at -30 to -35° C. for 10 minutes. Moreadditions of reagents were carried out in the following manner: (1)additional bromochloromethane (14 mL) was added, followed byn-butyllithium (102 mL) at <-25° C. After addition the mixture wasstirred at -30 to -35° C. for 10 minutes. This was repeated once. (2)Additional bromochloromethane (7 mL, 0.11 mol) was added, followed byn-butyllithium (51 mL, 0.082 mol) at <-25° C. After addition the mixturewas stirred at -30 to -35° C. for 10 minutes. This was repeated 5 times.(3) Additional bromochloromethane (7 mL, 0.11 mol) was added, followedby n-butyllithium (51 mL, 0.082 mol) at <-25° C. After addition themixture was stirred at -30 to -35° C. for 10 minutes. This was repeatedonce. The external cooling was stopped and the mixture warmed to ambienttemp. over 4 to 16 hours when TLC (silica gel, 20% ethyl acetate/hexane)indicated that the reaction was completed The reaction mixture wascooled to 10° C. and quenched with 1452 g of 16% ammonium chloridesolution (prepared by dissolving 232 g of ammonium chloride in 1220 mLof water), keeping the temperature below 23° C. The mixture was stirredfor 10 minutes and the organic and aqueous layers were separated. Theaqueous phase was extracted with ethyl acetate (2×500 mL). The ethylacetate layer was combined with the tetrahydrofuran layer. The combinedsolution was dried over magnesium sulfate (220 g), filtered andconcentrated on a rotary evaporator at 65° C. The brown oil residue wasdried at 70° C. in vacuo (0.8 bar) for 1 h to give 222.8 g of crudematerial.

EXAMPLE 2 ##STR27## Preparation ofN-[[3S-(phenylmethylcarbamoyl)aminol-2R-hydroxy-4-phenyl]-1-[(2-methylpropyl)amino-2-(1,1-dimethylethoxyl)carbonyl]butane

To a solution of 7.51 g (20.3 mmol) ofN-[[3S-(phenylmethylcarbamoyl)amino]-2R-hydroxy-4-phenylbutyl]-N-(2-methylpropyl)]aminein 67 mL of anhydrous tetrahydrofuran was added 2.25 g (22.3 mmol) oftriethylamine. After cooling to 0° C., 4.4 g (20.3 mmol) ofdi-tert-butyldicarbonate was added and stirring continued at roomtemperature for 21 hours. The volatiles were removed in vacuo, ethylacetate added, then washed with 5% citric acid, saturated sodiumbicarbonate, brine, dried over magnesium sulfate, filtered andconcentrated to afford 9.6 g of crude product. Chromatography on silicagel using 30% ethyl acetate/hexane afforded 8.2 g of pureN-[[3S-(phenylmethylcarbamoyl)amino]-2R-hydroxy-4-phenyl]-1-[(2-methylpropyl)amino-2-(1,1-dimethylethoxyl)carbonyl]butane,mass spectum m/e=477 (M+Li).

EXAMPLE 3A ##STR28## Preparation of phenylmethyl[2R-hydroxy-3-[(3-methylbutyl)(methylsulfonyl)amino]-1S-(phenylmethyl)-propyl]carbamate

To a solution ofN[3(S)-benzyloxycarbonylamino-2(R)-hydroxy-4-phenylbutyl] N-isoamylamine(2.0 gm, 5.2 mmol) and triethylamine (723 uL, 5.5 mmol) indichloromethane (20 mL) was added dropwise methanesulfonyl chloride (400uL, 5.2 mmol). The reaction mixture was stirred for 2 hours at roomtemperature, then the dichloromethane solution was concentrated to ca. 5mL and applied to a silica gel column (100 gm). The column was elutedwith chloroform containing 1% ethanol and 1% methanol. The phenylmethyl[2R-hydroxy-3-[(3-methylbutyl)(methylsulfonyl)amino]-1S-(phenylmethyl)propyl]carbamate was obtained asa white solid Anal. Calcd for C₂₄ H₃₄ N₂ O₅ S: C, 62.31; H, 7.41; N,6.06. Found: C, 62.17; H, 7.55; N, 5.97.

EXAMPLE 3B ##STR29## Preparation of phenylmethyl[2R-hydroxy-3-[(3-methylbutyl)(phenylsulfonyl)amino]-1S-(phenylmethyl)-propyl]carbamate

From the reaction ofN[3(S)-benzyloxycarbonylamino-2(R)-hydroxy-4-phenylbutyl] N-isoamylamine(1.47 gm, 3.8 mmol), triethylamine (528 uL, 3.8 mmol) andbenzenesulfonyl chloride (483 uL, 3.8 mmol) one obtains phenylmethyl[2R-hydroxy-3-[(3-methylbutyl)(phenylsulfonyl)amino]-1S-(phenylmethyl)propyl]-carbamate. Columnchromotography on silica gel eluting with chloroform containing 1%ethanol afforded the pure product. Anal. Calcd for C₂₉ H₃₆ N₂ O₅ S: C,66.39; H, 6.92; N, 5.34. Found: C, 66.37; H, 6.93; N, 5.26.

EXAMPLE 4 ##STR30## Preparation of Phenylmethyl[2R-hydroxy-3-[(3-methylbutyl)(n-propanesulfonyl)amino]-1S-(phenylmethyl)-propyl]carbamate

To a solution ofN[3(S)-benzyloxycarbonylamino-2(R)-hydroxy-4-phenylbutyl] N-isoamylamine(192 mg , 0.5 mmol) and triethylamine (139 uL, 1.0 mmol) indichloromethane (10 mL) was added dropwise trimethylsilyl chloride (63uL, 0.5 mmol). The reaction was allowed to stir for 1 hour at roomtemperature, cooled to 0° C. with an ice bath and then n-propanesulfonylchloride (56 uL, 0.5 mmol) was added dropwise. The reaction mixture wasstirred for 1.5 hours at room temperature, then diluted with ethylacetate (50 mL) and washed sequentially with 1N HCl, water, saturatedsodium bicarbonate solution, and saturated sodium chloride solution (25mL each). The organic solution was dried over magnesium sulfate,filtered and concentrated to an oil. The oil was stirred with methanol(10 mL) for 16 hours, concentrated and the residue chromatographed onsilica gel (50 gm ) eluting with 10% ethyl acetate in hexane (450 mL),then with 1:1 ethyl acetate/hexane. The phenylmethyl[2R-hydroxy-3-[(3-methylbutyl)(n-propanesulfonyl)amino]-1S-(phenylmethyl)propyl]carbamate wasrecrystallized from ethyl ether/hexane to afford a white solid Anal.Calcd. for C₂₆ H₃₈ N₂ O₅ S: C, 63.64; H, 7.81; N, 5.71. Found: C, 63.09;H, 7.74; N, 5.64.

EXAMPLE 5 ##STR31## The procedure described in Example 2 was used toprepare phenylmethyl [2S-hydroxy-3-[(3-methylbutyl)(methylsulfonyl)amino]-1S-(phenylmethyl)propyl]carbamate.

To a solution ofN[3(S)-benzyloxycarbonylamino-2(S)-hydroxy-4-phenylbutyl] N-isoamylamine(192 mg, 0.5 mmol) and triethylamine (139 uL, 0.55 mmol) indichloromethane (8 mL) was added dropwise methanesulfonyl chloride (39uL, 0.55 mmol). The reaction mixture was stirred for 16 hours at roomtemperature, then the dichloromethane solution was applied to a silicagel column (50 gm). The column was eluted with dichloromethanecontaining 2.5% methanol. The phenylmethyl[2S-hydroxy-3-[(3-methylbutyl)(methylsulfonyl)amino]-1S-(phenylmethyl)propyl]carbamate was obtained asa white solid Anal. Calcd. for C₂₄ H₃₄ N₂ O₅ S ⋄ 0.2 H₂ O: C, 61.83; H,7.44; N, 6.01. Found: C, 61.62; H, 7.40; N, 5.99.

EXAMPLE 6

Following the procedures of the previous Examples 1-5, the intermediatecompounds set forth in Tables 1A and 1B were prepared.

                                      TABLE 1A                                    __________________________________________________________________________      #STR32##                                                                       -                                                                          Entry R.sup.3             R.sup.4                                             __________________________________________________________________________       1 isoamyl p-fluorophenyl                                                      2 isoamyl p-nitrophenyl                                                       3 isoamyl o-nitrophenyl                                                       4 isoamyl β-naphthyl                                                     5 isoamyl 2-thienyl                                                           6 isoamyl benzyl                                                              7 isobutyl p-fluorophenyl                                                     8 p-fluorobenzyl phenyl                                                       9 4-pyridylmethyl phenyl                                                     10 cyclohexylmethyl phenyl                                                    11 allyl phenyl                                                               12 propyl phenyl                                                              13 cyclopropylmethyl phenyl                                                   14 methyl phenyl                                                              15 propargyl phenyl                                                           16 isoamyl p-chlorophenyl                                                     17 isoamyl p-methoxyphenyl                                                    18 isoamyl m-nitrophenyl                                                      19 isoamyl m-trifluoromethylphenyl                                            20 isoamyl o-methoxycarbonylphenyl                                            21 isoamyl p-acetamidophenyl                                                  22 isobutyl phenyl                                                            23 --CH.sub.2 Ph --Ph                                                          - 24                                                                                                   --Ph 3##                                             - 25                                                                                                   --Ph 4##                                             - 26                                                                                                   --Ph 5##                                             - 27                                                                                                   --Ph 6##                                             - 28                                                                                                   --Ph 7##                                             - 29 --CH.sub.2 CH═CH.sub.2 --Ph                                          - 30                                                                                                   --Ph 8##                                             - 31                                                                                                   --Ph 9##                                             - 32 --CH.sub.2 CH.sub.2 Ph --Ph                                             33 --CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 OH --Ph                              34 --CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2 --Ph                                  - 35                                                                                                   --Ph 0##                                             - 36 --CH.sub.3 --Ph                                                         37 --CH.sub.2 CH.sub.2 CH.sub.2 SCH.sub.3 --Ph                                38 --CH.sub.2 CH.sub.2 CH.sub.2 S(O).sub.2 CH.sub.3 --Ph                       - 39 --CH.sub.2 CH.sub.2 CH(CH.sub.3).sub.2                                                            #STR41##                                             - 40 --CH.sub.2 CH.sub.2 CH(CH.sub.3).sub.2 --CH.sub.2 CH.sub.2                                      CH.sub.3                                              41 --CH.sub.2 CH.sub.2 CH(CH.sub.3).sub.2 --CH.sub.3                           - 42 --CH.sub.2 CH.sub.2 CH(CH.sub.3).sub.2                                                            #STR42##                                             - 43 --CH.sub.2 CH.sub.2 CH(CH.sub.3).sub.2                                                            #STR43##                                             - 44 --CH.sub.2 CH.sub.2 CH(CH.sub.3).sub.2                                                            #STR44##                                             - 45 --CH.sub.2 CH(CH.sub.3).sub.2                                                                     #STR45##                                             - 46 --CH.sub.2 CH(CH.sub.3).sub.2                                                                     #STR46##                                             - 47 --CH.sub.2 CH(CH.sub.3).sub.2                                                                     #STR47##                                             - 48 --CH.sub.2 CH.sub.2 CH.sub.3                                                                      #STR48##                                             - 49 --CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                             #STR49##                                             - 50 --CH.sub.2 CH.sub.2 CH(CH.sub.3).sub.2 --CF.sub.3                       51 --CH.sub.2 CH(CH.sub.3).sub.2 --CH.sub.3                                   52 --CH.sub.2 CH.sub.2 CH(CH.sub.3).sub.2 --CH.sub.2 Cl                        - 53 --CH.sub.2 CH(CH.sub.3).sub.2                                                                     #STR50##                                             - 54 --CH.sub.2 CH(CH.sub.3).sub.2                                                                     #STR51##                                             - 55 --CH.sub.2 CH(CH.sub.3).sub.2 --CH═CH.sub.2                          - 56 --CH.sub.2 --CH)CH.sub.3)(CH.sub.2 CH.sub.3)                                                     ##STR52##                                          __________________________________________________________________________      #STR53##                                                                                                 MASS MEASUREMENT                                 Entry                                                                            R.sup.3   R.sup.4         MOL FORM                                                                             CALC FOUND                                __________________________________________________________________________       1                                                                                                                     #STR54##                                                                      C.sub.29 H.sub.36 N.sub.2                                                   O.sub.5 S 531  (M + Li) 531                                                     -  2                                                                          C.sub.29 H.sub.36 N.sub.2                                                   O.sub.6 S 541  (M + H) 541                                                      -  3                                                                          C.sub.30 H.sub.36 N.sub.2                                                   O.sub.6 S 555.2529  (M + H)                                                   555.2582                                -  4                                                                                                                  #STR58##                              -  5                                                                                                                  #STR59##                              -  6                                                                                                                  C.sub.28 H.sub.33 N.sub.2                                                   O.sub.5 SF 529.2172  (M + H)                                                  521.2976                                -  7                                                                                                                  #STR61##                              -  8                                                                                                                  C.sub.29 H.sub.36 N.sub.2                                                   O.sub.5 S.sub.2 563  (M + Li)                                                 563                                     -  9                                                                                                                  C.sub.29 H.sub.36 N.sub.2                                                   O.sub.6 S.sub.2 573  (M + H) 573        - 10                                                                                                                  C.sub.29 H.sub.36 N.sub.2                                                   O.sub.7 S.sub.2 595  (M + Li)        __________________________________________________________________________                                             595                              

                  TABLE 1B                                                        ______________________________________                                          #STR65##                                                                      Entry     R                  R.sup.3                                        ______________________________________                                          1                                                                                                        #STR66##                                                                    --CH.sub.2 Ph                                         - 2                                                                                                     --CH.sub.2 CH.sub.2 CH(CH.sub.3).sub.2                                        - 3                                                                           --CH.sub.2 CH(CH.sub.3).sub.2                       - 4                                                                                                     --CH.sub.2 CH(CH.sub.3).sub.2                       - 5                                                                                                     --CH.sub.2 CH(CH.sub.3).sub.2                       - 6                                                                                                     --CH.sub.2 CH(CH.sub.3).sub.2                       - 7                                                                                                     --CH.sub.2 CH(CH.sub.3).sub.2                       - 8                                                                                                     --CH.sub.2 CH(CH.sub.3).sub.2                       - 9                                                                                                     --CH.sub.2 CH.sub.2 (CH.sub.3).sub.2             ______________________________________                                    

                                      TABLE 1C                                    __________________________________________________________________________      #STR75##                                                                       -                       Mass Determination                                 X    R.sup.8      FORMULA  Calc  Found                                        __________________________________________________________________________      H                                                                                                              CSTR76##                                                                    .sub.27 H.sub.33 N.sub.3 O.sub.5 S                                            512.2219  (M + H) 521.2267                      - OCH.sub.3                                                                                                   C.sub.28 H.sub.35 N.sub.3 O.sub.6 S                                         548.2407  (M + Li) 548.2434                     - F                                                                                                           C.sub.27 H.sub.32 N.sub.3 O.sub.5 SF                                        530  (M + H) 530                                - Cl                                                                                                          C.sub.27 H.sub.32 N.sub.3 O.sub.5 SCl                                       546  (M + H) 546                                - NO.sub.2                                                                                                    C.sub.27 H.sub.32 N.sub.4 O.sub.7 S                                         557  (M + H) 557                                - OH                                                                                                          C.sub.27 H.sub.33 N.sub.3 O.sub.6 S                                         528  (M + H) 528                                - OCH.sub.3                                                                                                   C.sub.28 H.sub.35 N.sub.3 O.sub.6 S                                         542.2325  (M + H) 542.2362                      - OCH.sub.3                                                                                                   C.sub.28 H.sub.35 N.sub.3 O.sub.6 S                                         548.2407  (M + Li) 548.2393                     - OCH.sub.3                                                                                                   C.sub.27 H.sub.34 N.sub.4 O.sub.6 S                                         543  (M + H) 543                                - OCH.sub.3                                                                                                   C.sub.29 H.sub.36 O.sub.6 N.sub.2 S                                         547.2454  (M + Li) 547.2475                     - OCH.sub.3 tert-Butyl C.sub.26 H.sub.38 N.sub.2 O.sub.6 S 513.2611                                         (M + Li) 513.2593                               - OCH.sub.3                                                                                                   C.sub.28 H.sub.35 N.sub.3 O.sub.7 S                                         564  (M + Li) 564                               - OCH.sub.3                                                                                                   C.sub.28 H.sub.35 N.sub.3 O.sub.7 S                                         564  (M + Li) 564                            __________________________________________________________________________

The following Examples 7-9 illustrate preparation of β-amino acidintermediates. These intermediates can be coupled to the intermediatecompounds of Examples 1-6 to produce inhibitor compounds of the presentinvention containing β-amino acids.

EXAMPLE 7

A. Preparation of 4(4-methoxybenzyl)itaconate ##STR88##

A 5 L three-necked round bottomed flask equipped with constant pressureaddition funnel, reflux condenser, nitrogen inlet, and mechanicalstirrer was charged with itaconic anhydride (660.8 g, 5.88 mol) andtoluene (2300 mL). The solution was warmed to reflux and treated with4-methoxybenzyl alcohol (812.4 g, 5.88 mol) dropwise over a 2.6 hperiod. The solution was maintained at reflux for an additional 1.5 hand then the contents were poured into three 2 L erlenmeyer flasks tocrystallize. The solution was allowed to cool to room temperaturewhereupon the desired mono-ester crystallized. The product was isolatedby filtration on a Buchner funnel and air dried to give 850.2 g, 58% ofmaterial with mp 83-85° C., a second crop, 17% was isolated aftercooling of the filtrate in an ice bath. ¹ H NMR (CDCl₃) 300 MHz 7.32(d,J=8.7 Hz, 2H), 6.91(d, J=8.7 Hz, 2H), 6.49(s, 1H), 5.85(s, 1H), 5.12(s,2H), 3.83(s, 3H), 3.40(s, 2H).

B. Preparation of Methyl 4(4-methoxybenzyl) itaconate ##STR89##

A 5 L three-necked round bottomed flask equipped with reflux condenser,nitrogen inlet, constant pressure addition funnel and mechanical stirrerwas charged with 4(4-methoxybenzyl) itaconate (453.4 g, 1.81 mol) andtreated with 1,5-diazabicyclo[4.3.0]non-5-ene (275.6 g, 1.81 mol),(DBN), dropwise so that the temperature did not rise above 15° C. Tothis stirring mixture was added a solution of methyl iodide (256.9 g,1.81 mol) in 250 mL of toluene from the dropping funnel over a 45mperiod. The solution was allowed to warm to room temperature and stirredfor an additional 3.25 h.

The precipitated DBN hydroiodide was removed by filtration, washed withtoluene and the filtrate poured into a separatory funnel. The solutionwas washed with sat. aq. NaHCO₃ (2×500 mL), 0.2N HCl (1×500 mL), andbrine (2×500 mL), dried over anhyd. MgSO₄, filtered, and the solventremoved in vacuo. This gave a clear colorless oil, 450.2 g, 94% whoseNMR was consistent with the assigned structure. ¹ H NMR (CDCl₃ 300 MHz7.30(d, J=8.7 Hz, 2H), 6.90(d, J=8.7 Hz, 2H), 6.34(s, 1H), 5.71(s, 1H),5.09(s, 2H), 3.82(s, 3H), 3.73(s, 3H), 3.38(s, 2H). ¹³ C NMR (CDCl₃)170.46, 166.47, 159.51, 133.55, 129.97, 128.45, 127.72, 113.77, 66.36,55.12, 51.94, 37.64.

C. Preparation of Methyl 4(4-methoxybenzyl) 2(R)-methylsuccinate##STR90##

A 500 mL Fisher-Porter bottle was charged with methyl 4(4-methoxybenzyl)itaconate (71.1 g, 0.269 mol), rhodium (R,R) DIPAMP catalyst (204 mg,0.269 mmol, 0.1 mol %) and degassed methanol (215 mL). The bottle wasflushed 5 times with nitrogen and 5 times with hydrogen to a finalpressure of 40 psig. The hydrogenation commenced immediately and afterca. lh the uptake began to taper off, after 3 h the hydrogen uptakeceased and the bottle was flushed with nitrogen, opened and the contentsconcentrated on a rotary evaporator to give a brown oil that was takenup in boiling iso-octane (ca. 200 mL, this was repeated twice), filteredthrough a pad of celite and the filtrate concentrated in vacuo to give66.6 g, 93% of a clear colorless oil, ¹ H NMR (CDC13 300 MHz 7.30(d,J=8.7 Hz, 2H), 6.91(d, J=8.7 Hz, 2H), 5.08(s, 2H), 3.82(s, 3H), 3.67(s,3H), 2.95(ddq, J=5.7, 7.5, 8.7 Hz, 1H), 2.79(dd, J=8.1, 16.5 Hz, 1H),2.45(dd, J=5.7, 16.5 Hz, 1H), 1.23(d, J=7.5 Hz, 3H).

D. Preparation of Methyl 2(R)-methylsuccinate

A 3 L three-necked round-bottomed flask equipped with a nitrogen inlet,mechanical stirrer, reflux condenser and constant pressure additionfunnel was charged with methyl 4(4-methoxybenzyl) 2(R)-methylsuccinate(432.6 g, 1.65 mol) and toluene (1200 mL). The stirrer was started andthe solution treated with trifluoroacetic acid (600 mL) from thedropping funnel over 0.25 h. The solution turned a deep purple color andthe internal temperature rose to 45° C. After stirring for 2.25 h thetemperature was 27° C. and the solution had acquired a pink color. Thesolution was concentrated on a rotary evaporator. The residue wasdiluted with water (2200 mL) and sat. aq. NaHCO₃ (1000 mL). AdditionalNaHCO₃ was added until the acid had been neutralized. The aqueous phasewas extracted with ethyl acetate (2×1000 mL) to remove the by-productsand the aqueous layer was acidified to pH=1.8 with conc. HCl. Thissolution was extracted with ethyl acetate (4×1000 mL), washed withbrine, dried over anhyd. MgSO₄, filtered and concentrated on a rotaryevaporator to give a colorless liquid 251 g, >100% that was vacuumdistilled through a short path apparatus cut 1: bath temperature 120° C.@ >1 mm, bp 25-29° C.; cut 2: bath temperature 140° C. @ 0.5 mm, bp95-108° C., 151 g, [α]_(d) @ 25° C.=+1.38° C.(c=15.475, MeOH), [α]_(d)=+8.48° C. (neat); cut 3: bath temperature 140° C., bp 108° C., 36 g,[α]_(d) @ 25° C.=+1.49° C.(c=15.00, MeOH), [α]_(d) =+8.98° C. (neat).Cuts 2 and 3 were combined to give 189 g, 78% of product, ¹ H NMR(CDCl₃) 300 MHz 11.6(brs, 1H), 3.72(s, 3H), 2.92(ddq, J=l5.7, 6.9, 8.0Hz, 1H), 2.81(dd, J=8.0, 16.8 Hz, 1H), 2.47(dd, J=5.7, 16.8 Hz, 1H),1.26(d, J=6.9 Hz, 3H).

E. Preparation of Methyl Itaconate ##STR91##

A 50 mL round bottomed flask equipped with reflux condenser, nitrogeninlet and magnetic stir bar was charged with methyl 4(4-methoxybenzyl)itaconate (4.00 g, 16 mmol), 12 mL of touluene and 6 mL oftrifluoroacetic acid. The solution was kept at room temperature for 18hours and then the volatiles were removed in vacuo. The residue wastaken up in ethyl acetate and extracted three times with saturatedaqueous sodium bicarbonate solution. The combined aqueous extract wasacidified to pH=1 with aqueous potassium bisulfate and then extractedthree times with ethyl acetate. The combined ethyl acetate solution waswashed with saturated aqueous sodium chloride, dried over anhydrousmagnesium sulfate, filtered, and concentrated in vacuo. The residue wasthen vacuum distilled to give 1.23 g, 75% of pure product, bp 85-87 @0.1 mm. ¹ H NMR (CDCl₃) 300 MHz 6.34(s, 1H), 5.73(s, 2H), 3.76(s, 3H)3.38(s, 2H). ¹³ C NMR (CDCl₃) 177.03, 166.65, 129.220, 132.99, 52.27,37.46.

F. Curtius Rearrangement of Methyl 2(R)-methylsuccinate: Preparation ofMethyl N-Moz-α-methyl β-alanine. ##STR92##

A 5 L four necked round bottomed flask equipped with a nitrogen inlet,reflux condenser, mechanical stirrer, constant pressure addition funnel,and thermometer adapter was charged with methyl 2(R)-methylsuccinate(184.1 g, 1.26 mol), triethylamine (165.6 g, 218 mL, 1.64 mol, 1.3equivalents), and toluene (1063 mL). The solution was warmed to 85° C.and then treated dropwise with a solution of diphenylphosphoryl azide(346.8 g, 1.26 mol) over a period of 1.2 h. The solution was maintainedat that temperature for an additional l.Oh and then the mixture wastreated with 4-methoxybenzyl alcohol (174.1 g, 1.26 mol) over a 0.33 hperiod from the dropping funnel. The solution was stirred at 88° C. foran additional 2.25 h and then cooled to room temperature. The contentsof the flask were poured into a separatory funnel and washed with sat.aq. NaHCO₃ (2×500 mL), 0.2N HCl (2×500 mL), brine (1×500 mL), dried overanhyd. MgSO₄, filtered, and concentrated in vacuo to give 302.3 g, 85%of the desired product as a slightly brown oil. ₁ H NMR (CDCl₃) 300 MHz7.32(d, J=8.4 Hz, 2H), 6.91(d, J=8.4 Hz, 2H), 5.2(brm, 1H), 5.05(s, 2H),3.83(s, 3H), 3.70(s, 3H), 3.35(m, 2H), 2.70(m, 2H), 1.20(d, J=7.2 Hz,3H).

G. Hydrolysis of Methyl N-Moz-α-methyl β-alanine: Preparation ofα-methyl β-alanine Hydrochloride ##STR93##

A 5 L three-necked round bottomed flask equipped with a refluxcondenser, nitrogen inlet and mechanical stirrer was charged with methylN-Moz-α-methyl β-alanine (218.6 g, 0.78 mol), glacial acetic acid (975mL) and 12N hydrochloric acid (1960 mL). The solution was then heated toreflux for 3 h. After the solution had cooled to room temperature (ca. 1h) the aqueous phase was decanted from organic residue (polymer) and theaqueous phase concentrated on a rotary evaporator. Upon addition ofacetone to the concentrated residue a slightly yellow solid formed thatwas slurried with acetone and the white solid was isolated by filtrationon a Buchner funnel. The last traces of acetone were removed byevacuation to give 97.7 g, 90% of pure product, mp 128.5-130.5° C.[α]_(d) @ 25° C.=9.0° C. (c=2.535, Methanol). ¹ H NMR (D₂ O) 300 MHz3.29(dd, J=8.6, 13.0 Hz, 1H), 3.16(dd, J=5.0, 13.0 m Hz, 1H), 2.94(ddq,J=7.2, 5.0, 8.6 Hz, 1H), 1.30(d,J=7.2 Hz, 3H); ¹³ C NMR (D₂ O) 180.84,44.56, 40.27, 17.49.

H. Preparation of N-Boc α-Methyl β-Alanine ##STR94##

A solution of a-methyl b-alanine hydrochloride (97.7 g, 0.70 mol) inwater (1050 mL) and dioxane (1050 mL) the pH was adjusted to 8.9 with2.9N NaOH solution. This stirring solution was then treated withdi-tert-butyl pyrocarbonate (183.3 g, 0.84 mol, 1.2 equivalents) all atonce. The pH of the solution was maintained between 8.7 and 9.0 by theperiodic addition of 2.5N NaOH solution. After 2.5 h the pH hadstabilized and the reaction was judged to be complete. The solution wasconcentrated on a rotary evaporator (the temperature was maintained at<40° C.). The excess di-tert-butyl pyrocarbonate was removed byextraction with dichloromethane and then the aqueous solution wasacidified with cold 1N HCl and immediately extracted with ethyl acetate(4×1000 mL). The combined ethyl acetate extract was washed with brine,dried over anhyd. MgSO₄, filtered and concentrated on a rotaryevaporator to give a thick oil 127.3 g, 90% crude yield that was stirredwith n-hexane whereupon crystals of pure product formed, 95.65 g, 67%,mp 76-78° C., [α]_(d) @ 25° C.=-11.8° C. (c=2.4, EtOH). A second cropwas obtained by concentration of the filtrate and dilution with hexane,15.4 g, for a combined yield of 111.05 g, 78%. ¹ H NMR (acetone D₆) 300MHz 11.7 (brs, 1H), 6.05 (brs 1H), 3.35 (m, 1H), 3.22 (m, 1H), 2.50 (m,1H), 1.45(s, 9H), 1.19 (d, J=7.3 Hz, 3H); ¹³ C NMR (acetone D₆) 177.01,79.28, 44.44, 40.92, 29.08, 15.50. Elemental analysis calcd. for C₉ H₁₇NO₄ : C, 53.19, H, 8.42; N, 6.89. Found: C, 53.36; H, 8.46; N, 6.99.

I. Preparation of N-4-Methoxybenzyloxycarbonyl α-Methyl β-Alanine

A solution of N-4-methoxybenzyloxycarbonyl α-methyl β-alanine methylester (2.81 g, 10.0 mmol) in 30 mL of 25% aqueous methanol was treatedwith lithium hydroxide (1.3 equivalents) at room temperature for aperiod of 2 h. The solution was concentrated in vacuo and the residuetaken up in a mixture of water and ether and the phases separated andthe organic phase discarded. The aqueous phase was acidified withaqueous potassium hydrogen sulfate to pH=1.5 and then extracted threetimes with ether. The combined ethereal phase was washed with saturatedaqueous sodium chloride solution, dried over anhydrous magnesiumsulfate, filtered and concentrated in vacuo to give 2.60 g, 97% ofN-4-Methoxybenzyloxycarbonyl α-methyl β-alanine (N-Moz-AMBA) which waspurified by recrystallization from a mixture of ethyl acetate and hexaneto give 2.44 g, 91% of pure product, mp 96-97° C., MH+=268. ¹ H NMR (D₆-acetone/300 MHz) 1.16 (3H, d, J=7.2Hz), 2.70 (1H, m), 3.31 (2H, m),3.31 (3H, s), 4.99 (2H, s), 6.92 (2H, 4, J=8.7 Hz), 7.13 (2H, d, J=8.7Hz).

EXAMPLE 8

Following generally the procedure of Example 7, the β-amino acids setforth in Table 1 were prepared.

                                      TABLE 2                                     __________________________________________________________________________      #STR95##                                                                       -                                                                          Entry                                                                            R.sup.1          R.sup.1 '      R.sup.1 "                                  __________________________________________________________________________     1 --CH.sub.3       H              H                                             2 --CH(CH.sub.3).sub.2 H H                                                    3 --C(CH.sub.3).sub.3 H H                                                     4 H H H                                                                       5 H --CH.sub.3 H                                                              6 H --CH.sub.3 --CH.sub.3                                                     7 H H --CO2CH.sub.3                                                           8 H H --CONH.sub.2                                                            9 --CH.sub.2 CH.sub.3 H H                                                    10 --CH.sub.2 CH(CH.sub.3).sub.2 H H                                          11 --CH.sub.2 C.sub.6 H.sub.5 H H                                              - 12                                                                                                            H H 96##                                    - 13                                                                                                            H H 97##                                    - 14 --CH.sub.2 COOH H H                                                     15 H --CH(CH.sub.3).sub.2 H                                                   16 H --CH.sub.2 CH(CH.sub.3).sub.2 H                                           - 17 H                                                                                                          H TR98##                                    - 18 H                                                                                                          H TR99##                                    - 19 H                                                                                                          H TR100##                                   - 20 H                                                                                                          H TR101##                                   - 21 H --(CH.sub.2).sub.3 CH(C.sub.6 H.sub.5).sub.2 H                      __________________________________________________________________________

EXAMPLE 9

Utilizing generally the procedure set forth in Example 7, the followingβ-amino acid compounds were prepared. ##STR102##

EXAMPLE 10A ##STR103## Preparation of 4-Pyridinecarboxamide,N-[2R-hydroxy-3-[[(4-methoxyyhenyl)sulfonyl](2-methylpropyl)amino]-1S-(-phenylmethyl)propyl]

To a solution of 231 mg (0.57 mmol) of2R-hydroxy-3-[(2-methylpropyl)(4-methoxyphenyl)sulfonyl]amino-1S-(phenylmethyl)propylamine in 3 mL of methylene chloride at 0 C,was added 288 mg(2.85 mmol) of triethylamine and then 112 mg(0.63 mmol)of isonicotinoyl chloride hydrochloride. After 19 hours at roomtemperature, the solvent was removed, ethyl acetate added, then washedwith saturated sodium bicarbonate, brine, dried with magnesium sulfate,filtered and concentrated to afford 290 mg of crude product. This waschromatographed on silica gel using 3-5% isopropanol/methylene chlorideas eluent to afford 190 mg of the desired compound; mass spectrum calc.for C₂₇ H₃₄ N₃ O₅ S (M+H) 512.2219; found 512.2280.

EXAMPLE 10B ##STR104## Preparation of Benzamide,N-[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(-phenylmethyl)propyl]-2,6-dimethyl

To a solution of 83 mg (0.55 mmol) of 2,6-dimethylbenzoic acid and 125mg (0.82 mmol) of N-hydroxybenzotriazole in 3 mL of anhydrous DMF at 0 Cwas added 117 mg (0.61 mmol) of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. After 2hours at 0 C, 203 mg (0.50 mmol) of2R-hydroxy-3-[(2-methylpropyl)(4-methoxyphenyl)sulfonyl]amino-1S-(phenylmethyl)propylaminewas added. After 22 hours at room temperature, the solvent was removedin vacuo, ethyl acetate added, then washed with saturated sodiumbicarbonate, brine, dried over magnesium sulfate, filtered andconcentrated to afford 300 mg of crude product. Chromatography on silicagel using 20-50% ethyl acetate/hexane afforded 37 mg of the desiredproduct; mass spectrum calcd for C₃₀ H₃₈ N₂ O₅ S (M+H) 539.2580; found539.2632.

EXAMPLE 10C ##STR105## Preparation of Benzamide,N-[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-2-methyl.

Part A. Preparation of 4-Nitro-2-methylbenzoic Acid.

A mixture of 1.0 g(3.8 mmol) of 2-iodo-nitrotoluene, 2.1 g(15.2 mmol)potassium carbonate and 27 mg(0.038 mmol) of palladium(II) dichloridebis(triphenylphosphine) in a mixture of 5 mL of water and 10 mL ofN,N-dimethylformamide. This was placed in a Fisher/Porter bottle under15 psig of carbon monoxideand heated at 70 C for 16 hours. The solutionbecame homogeneous when heated. The reaction was cooled, diethyl etherand water was added, the organic layer separated and discarded. Theaqueous layer was acidified with iN hydrohloric acid, extracted withethyl acetate, washed with water, brine, dried over magnesium sulfate,filtered and concentrated to yield 0.5 g of crude material. Thisdissolved in ethyl acetate, hexane added and the resulting brown soliddiscarded. The filtrate was concentrated, and then recrystallized fomdiethyl ether/hexane to afford 215 mg of 4-nitro-2-methylbenzoic acid,m/e=182(M+H).

Part B. Preparation of Benzamide,N-[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-2-methyl-4-nitro.

To a solution of 181 mg(1.0 mmol) of 4-nitro-2-methylbenzoic acid and230 mg(1.5 mmol) N-hydroxybenzotriazole in 3 mL of anhydrousN,N-dimethylformamide at 0 C, was added 211 mg(1.1 mmol) of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. Afterstirring at 0 C for 1 hour, 406 mg(1 mmol) of2R-hydroxy-3-[(2-methylpropyl)(4-methoxyphenyl)sulfonyl]amino-1S-(phenylmethyl)propylaminewas added. After 17 hours at room temperature, the solvent was removedunder reduced pressure, ethyl acetate added, washed with 5% citric acid,saturated sodium bicarbonate, brine, dried with magnesium sulfate,filtered and concentrated to yield 0.55 g of crude product. This waschromatographed on silica gel using 20-50% ethyl acetate/hexane aseluent to afford 0.49 g of the desired benzamide,N-[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-2-methyl-4-nitro,m/e=570(M+H).

Part C. Preparation of Benzamide,N-[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-2-methyl-4-amino.

A solution of 400 mg(0.70 mmol) of benzamide,N-[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-2-methyl-4-nitrofrom part B in 20 mL of methanol was hydrogenated over 0.2 g of 10%palladium on carbon catalyst under 50 psig of hydrogen for 2.5 hours.The catalyst was removed by filtration and the solution concentrated toafford 370 mg of the desired benzamide,N-[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-2-methyl-4-amino,m/e=540(M+H).

Part D. Preparation of Benzamide,N-[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-2-methyl-4-dimethylamino.

A solution of 0.17 g(0.31 mmol) of benzamide,N-[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-2-methyl-4-aminofrom part C in 5 mL of methanol and 0.20 mL of 37% aqueous formaldehydewas hydrogenated over 90 mg of 10% palladium on carbon under 15 psig ofhydrogen for 16 hours. The catalyst was removed by filtration, thesolvents removed under reduced pressure to afford 0.16 g of crudematerial. Chromatography on silica gel using 50% ethyl acetate as eluentafforded 0.12 g of the desired benzamide,N-[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-2-methyl-4-dimethylamino,m/e=568 (M+H).

EXAMPLE 10D ##STR106## Preparation of Benzamide,N-[2R-hydroxy-3-[[(4-hydroxyphenyl)sulfonyl](2-methylpropyl)amino]1S-(phenylmethyl)propyl]-2-methyl.

To a solution of 500 mg(1 mmol) of2R-hydroxy-3-[(2-methylpropyl)(4-hydroxyphenyl)sulfonyl]amino-1S-(phenylmethyl)propylaminein 2 mL of methylene chloride and 2 mL of N,N-dimethylformamide, wasadded 0.42 mL of triethylamine, followed by 0.12 mL of ortho-toluoylchloride. After 17 hours, the solvent was removed under reducedpressure, the residue dissolved in ethyl acetate, was with 5% citricacid, saturated sodium bicarbonate and brine, dried over anhydrousmagnesium sulfate, filtered and concentrated to afford 490 mg of crudematerial. This was chromatographed over 100 g of silica gel using 20-50%ethyl acetate/hexane as eluent to afford 232 mg of the desired product,m/e=511(M+H).

EXAMPLE 11A ##STR107## Preparation of N1-[2R-hydroxy-3-[(3-methylbutyl)(methyl-sulfonyl)amino]1S-(phenylmethyl)propyl]l-2S-[(2-quinolinylcarbonyl)amino]butanediamide

Part A:

A solution of phenylmethyl[2R-hydroxy-3-[(3-methylbutyl)(methylsulfonyl)amino]-1S-(phenylmethyl)-propyl]carbamateprepared as in Example 3 (100 mg) in methanol (10 mL) was hydrogenatedover 10% palladium on carbon for 2 hours, filtered through diatomaceousearth and concentrated to give the product as an oil.

Part B:

A solution of N--CBZ-L-asparagine (61 mg, 0.23 mmol) andN-hydroxybenzotriazole (33 mg, 0.22 mmol) in DMF (2 mL) was cooled to 0°C. with an ice bath and then EDC (42 mg, 0.22 mmol) was added. Thesolution was stirred for 30 minutes at 0° C. and then the product ofPart A (69 mg, 0.21 mmol) in DMF (2 mL) was added. After 30 minutes at0° C. the reaction was allowed to warm to room temperature and stir for16 hours. The reaction mixture was then poured into a 50% saturatedaqueous solution of sodium bicarbonate (100 mL) and the resulting whiteprecipitate collected by suction filtration, washed with water and driedin vacuo. The phenylmethyl [3-amino-1S-[[2R-hydroxy-3-[(3-methylbutyl)(methylsulfonyl)amino]-1S-(phenylmethyl)amino]carbonyl]-3-oxopropyl]carbamatewas obtained as a white solid Anal. Calcd. for C₂₈ H₄₀ N₄ O₇ S . 0.5 H₂O: C, 57.42; H, 7.06; N, 9.57. Found: C, 57.72; H, 7.21; N, 9.24.

Part C:

A solution of phenylmethyl [3-amino-1S-[[2R-hydroxy-3-[(3-methylbutyl)(methylsulfonyl)amino]-1S-(phenylmethyl)amino]carbonyl]-3-oxopropyl]carbamate(135 mg, 0.23) in methanol (15 mL) was hydrogenated over 10% palladiumon carbon for 6 hours, filtered through diatomaceous earth andconcentrated to give the product as an oil.

Part D:

To a solution of the product from Part C (101 mg, 0.23 mmol) in DMF (5mL) was added 2-quinoline carboxylic acid N-hydroxysuccinimide ester (67mg, 0.25 mmol). The reaction was stirred at room temperature for 16hours, then poured into a 50% saturated solution of sodium bicarbonate(60 mL). The resulting solid was collected by suction filtration washedwith water and dried in vacuo. The N1-[2R-hydroxy-3-[(3-methylbutyl)(methylsulfonyl)-amino]-1S-(phenylmethyl)propyl]-2S-[(2-quinolinylcarbonyl)-amino]butanediamidewas obtained as a white solid Anal. Calcd. for C₃₀ H₃₉ N₅ O₆ S . 0.1 H₂O: C, 58.52; H, 6.71; N, 11.37. Found: C, 58.34; H, 6.35; N, 11.13.

EXAMPLE 11B ##STR108## Preparation of N1-[2R-hydroxy-3-[(3-methylbutyl)(phenylsulfonyl)amino]-1S-(phenylmethyl)propyl]-2S-[(2-quinolinylcarbonyl)amino]butanediamide.

Part A:

The CBZ protected compound phenylmethyl[2R-hydroxy-3-[(3-methylbutyl)(phenylsulfonyl)amino]-1S-(phenylmethyl)propyl]carbamate(200 mg, 0.38 mmol) was deprotected by hydrogenation over 10% palladiumon carbon and the resulting product obtained as an oil.

Part B:

The free amine from Part A was coupled with N-CBZ-L-asparagine (109 mg,0.41 mmol) in the presence of N-hydroxybenzotriazole (63 mg, 0.41 mmol)and EDC (77 mg, 0.40 mmol) to give phenylmethyl[3-amino-1S-[[2R-hydroxy-3-[(3-methylbutyl)(phenylsulfonyl)amino]-1S-(phenylmethyl)amino]carbonyl]-3-oxopropyl]carbamateas a white solid Anal. Calcd. for C₃₃ H₄₂ N₄ O₇ S: C, 62.05; H, 6.63; N,8.77. Found: C, 61.86; H, 6.60; N, 8.64.

Part C:

The product of Part B (110 mg, 0.17) was deprotected by hydrogenationover 10% palladium on carbon to give the product as an oil.

Part D:

The resulting free amine was coupled with 2-quinoline carboxylic acidN-hydroxysuccinimide ester (45 mg, 0.17 mmol) to giveN1-[2R-hydroxy-3-[(3-methylbutyl)(phenylsulfonyl)amino]-1S-(phenylmethyl)propyl]-2S-[(2-quinolinylcarbonyl)amino]butanediamideas a white solid Anal. Calcd for C₃₅ H₄₁ N₅ O₆ S: C, 63.71; H, 6.26; N,10.61. Found: C, 63.59; H, 6.42; N, 10.42.

EXAMPLE 12A ##STR109## Preparation of2S-[[(dimethylamino)acetyl]amino]-N-[2R-hydroxy-3-[(3-methylbutyl)(methylsulfonyl)amino]-1S-(phenylmethyl)propyl]-3,3-dimethylbutanamide

Part A:

To a solution of N-CBZ-L-tert-leucine (100 mg, 0.38 mmol) andN-hydroxybenzotriazole (52 mg, 0.34 mmol) in DMF (3 mL) was added EDC(65 mg, 0.34 mmol). The solution was stirred for 60 minutes at roomtemperature and then the product of Example 10, Part A (105 mg, 0.32mmol) in DMF (2 mL) was added. The reaction was stirred for 16 hours atroom temperature, then poured into a 50% saturated solution of sodiumbicarbonate (50 mL). The aqueous mixture was extracted twice with ethylacetate (25 mL). The combined ethyl acetate layers were washed withwater (25 mL) and dried over magnesium sulfate. Filtration andconcentration produced an oil which was chromatographed on silica gel(50 gm) eluting with 2.5 % methanol in dichloromethane. The phenylmethyl[lS-[[[2R-hydroxy-3-[(3-methylbutyl)-(methylsulfonyl)amino]-1S-(phenylmethyl)propyl]amino]-carbonyl]-2,2-dimethylpropyl]carbamatewas obtained as a gummy solid Anal. Calcd. for C₃₀ H₄₅ N₃ O₆ S ⋄ 2.2 H₂O: C, 58.55; H, 8.09; N, 6.83. Found: C, 58.38; H, 7.77; N, 7.10.

Part B:

A solution of phenylmethyl [1S-[[[2R-hydroxy-3-[(3-methylbutyl)(methylsulfonyl)amino]-1S-(phenylmethyl)propyl]amino]carbonyl]-2,2-dimethylpropyl]carbamate(100 mg, 0.17 mmol) in methanol (10 mL) was hydrogenated over 10%palladium on carbon for 2 hours. The reaction was filtered throughdiatomaceous earth and concentrated to an oil.

Part C:

N,N-dimethylglycine (20 mg, 0.19 mmol), N-hydroxybenzotriazole (28 mg,0.18 mmol) and EDC (35 mg, 0.18 mmol) were stirred in DMF (4 mL) at roomtemperature for 40 minutes. The product from Part B in DMF (4 mL) wasadded and the reaction mixture stirred for 16 hours, then poured into a50% saturated sodium bicarbonate solution (50 mL). The aqueous mixturewas extracted three times with dichloromethane (30 mL) which in turnwere washed with water (30 mL) and dried over magnesium sulfate.Filtration and concentration afforded an oil. The oil waschromatographed on silica gel (50 gm) eluting initially with 2.5%methanol in dichloromethane (400 mL) and then with 5% methanol indichloromethane. The2S-[[(dimethylamino)acetyl]amino]-N-[2R-hydroxy-3-[(3-methylbutyl)(methylsulfonyl)amino]-1S-(phenylmethyl)-propyl]-3,3-dimethylbutanamidewas obtained as a white solid Anal. Calcd. for C₂₆ H₄₆ N₄ O₅ S ⋄ 0.5 CH₂Cl₂ : C, 56.04; H, 8.34; N, 9.87. Found: C, 56.06; H, 8.36; N, 9.70.

EXAMPLE 12B ##STR110## Preparation of2S-[[(dimethylamino)acetyllamino]N-[2R-hydroxy-3-[(3-methyl-butyl)(phenylsulfonyl)amino]-1S-(phenylmethyl)-propyl]-3,3-dimethylbutaneamide

Part A:

To a solution of N-CBZ-L-tert-leucine (450 mg, 1.7 mmol) andN-hydroxybenzotriazole (260 mg, 1.7 mmol) in DMF (10 mL) was added EDC(307 mg, 1.6 mmol). The solution was stirred for 60 minutes at roomtemperature and then the product of Example 11, Part A (585 mg, 1.5mmol) in DMF (2 mL) was added. The reaction was stirred for 16 hours atroom temperature, then poured into a 50% saturated solution of sodiumbicarbonate (200 mL). The aqueous mixture was extracted thrice withethyl acetate (50 mL). The combined ethyl acetate layers were washedwith water (50 mL) and saturated NaCl solution (50 mL), then dried overmagnesium sulfate. Filtration and concentration produced an oil whichwas chromatographed on silica gel (50 gm) eluting with 20% ethyl acetatein hexane. The phenylmethyl [1S-[[[2R-hydroxy-3-[(3-methylbutyl)(phenylsulfonyl)amino]-1S-(phenylmethyl)propyl]amino]carbonyl]-2,2-dimethylpropyl]carbamatewas obtained as a solid Anal. Calcd for C₃₅ H₄₇ N₃ O₆ S: C, 65.91; H,7.43; N, 6.59. Found: C, 65.42; H, 7.24; N, 6.55.

Part B:

A solution of phenylmethyl [1S-[[[2R-hydroxy-3-[(3-methylbutyl)(phenylsulfonyl)-amino]-1S-(phenylmethyl)propyl]amino]carbonyl]-2,2-dimethylpropyl]carbamate(200 mg, 0.31 mmol) in methanol (15 mL) was hydrogenated over 10%palladium on carbon for 2 hours. The reaction was filtered throughdiatomaceous earth and concentrated to an oil.

Part C:

The resulting free amine from part B (150 mg, 0.3 mmol) was combinedwith diisopropylethylamine (114 uL, 0.33 mmol) in dichloromethane (5mL). To this was added bromoacetyl chloride (27 uL, 0.33 mmol) dropwise.The reaction was stirred for 30 minutes at room temperature, thendiluted with dichloromethane (30 mL) and extracted with 1 N HCl, water,and then saturated NaCl solution (25 mL each). The organic solution wasdried over MgSO₄ and concentrated to a solid. The2S-[[bromoacetyl]amino]-N-[2R-hydroxy-3-[(3-methylbutyl)(phenylsulfonyl)amino]-1S-(phenylmethyl)propyl]-3,3-dimethylbutaneamidewas sufficiently pure for use in the next step. This material can alsobe prepared by substituing bromoacetic anhydride for bromoacetylchloride, or one can use chloroacetyl chloride or chloracetic anhydride.

Part D:

The product from part C was dissolved in dichloromethane (5 mL) anddiisopropylethylamine (114 uL, 0.66 mmol) and dimethylaminehydrochloride (53 mg, 0.66 mmol) were added. The reaction was stirredfor 18 hours then concentrated under a stream of nitrogen to about 1 mL.The residue was chromatographed on silica gel (50 gm) using 2% methanolin dichloromethane. The 2S-[[(dimethylamino)-acetyl]amino]-N-[2R-hydroxy-3-[(3methylbutyl)-(phenylsulfonyl)amino]-1S-(phenylmethyl)propyl]-3,3-dimethylbutaneamide was obtained as a solid. Anal, Calcd forC₃₁ H₄₈ N₄ O₅ S: C, 63.24; H, 8.22; N, 9.52. Found: C, 63.03; H, 8.01;N, 9.40.

EXAMPLE 12C ##STR111## Preparation of2S-[[(methylamino)acetyl]aminol]-N-[2R-hydroxy-3-[(3-methyl-butyl)(phenylsulfonyl)amino]-1S-(phenylmethyl)propyl]-3,3-dimethylbutaneamide

2S-[[bromoacetyl]amino]-N-[2R-hydroxy-3-[(3-methylbutyl)(phenylsulfonyl)amino]-1S-(phenylmethyl)propyl]-3,3-dimethylbutaneamide(103 mg, 0.16 mmol) and 40% aqueous methylamine (42 uL, 0.49 mmol) werecombined in ethanol (2 mL) and stirred at room temperature for 24 hours.The reaction mixture was concentrated to dryness and triturated withether. The solid material was removed by filtration and the filtrateconcentrated to an oil. The oil was chromatographed on silica (50 gm)using 4% methanol in dichloromethane. The2S-[[(methylamino)acetyl]amino]-N-[2R-hydroxy-3-[(3-methylbutyl)(phenylsulfonyl)amino]-1S-(phenylmethyl)propyl]-3,3-dimethylbutaneamidewas obtained as a solid. Anal. Calcd for C₃₀ H₄₆ N₄ O₅ S: C, 62.69; H,8.07; N, 9.75. Found: C, 62.38; H, 8.14; N, 9.60.

EXAMPLE 12D ##STR112## Preparation of Pentanamide,2S-[[(Dimethylamino))acetyl]amino]-N-[2R-hydroxy-3-[(3-methylbutyl)phenylsulfonyl)amino]-1S-(phenylmethyl)propyl]3S-methyl--

Part A:

To a solution the amine product of Example 11, Part A; (2.79 g, 7.1mmol) in 27 mL of dioxane was added (2.3 g, 7.1 mmol) ofN-t-butylcarbonyl-L-isoleucine-N-hydroxysuccinamide ester, and thereaction was stirred under nitrogen atmosphere for 16 hours. Thecontents of the reaction were concentrated in vacuo, and the residuedissolved in ethyl acetate, washed with potassium hydrogen sulfate (5%aqueous), saturated sodium bicarbonate, and saturated sodium chloride.The organic layer was dried over magnesium sulfate, filtered andconcentrated to yield 4.3 grams of crude material which waschromatographed using 3:1 ethyl acetate: hexane to obtain 3.05 g, 72%yield of Pentanamide,2S-[[(1,1-dimethylethoxy)carbonyl]amino]-N-[2R-hydroxy-3-[(3-methylbutyl)phenylsulfonyl)amino]-1S-(phenylmethyl)propyl]-3-methyl-.

Part B

(3.05 g, 5.0 mmol) of the product from Part A; was dissolved in 20 mL of4N HCl in dioxane and stirred under nitrogen atmosphere for 1.5 hours.The contents were concentrated in vacuo, and chased with diethyl ether.The crude hydrochloride salt was pumped on at 1 mm Hg until dry to yield2.54 g of product as its hydrochloride salt.

Part C:

(2.54 g, 5.0 mmol) of amine hydrochloride was dissolved in 50 mL oftetrahydrofuran and to this was added (1.01 g, 10 mmol) of4-methyl-morpholine, at which time a precipitate forms. To thissuspension was added chloroacetic anhydride (0.865 g, 5.0 mmol) andstirred for 40 minutes. The contents were concentrated in vacuo, and theresidue partitioned in ethyl acetate (200 mL) and 5% KHSO₄. The organiclayer was washed with saturated sodium bicarbonate, and saturated sodiumchloride, dried over magnesium sulfate, filtered and concentrated toyield the crude product. Purification by silica gel chromatography usingan eluant of 1:1 ethyl acetate; hexanes yielded 1.89 grams of purechloroacetamide.

Part D:

To a solution of chloroacetamide (1.89 g, 3.2 mmol) from Part C, in 25mL of tetrahydrofuran was added 4.0 mL of 50% aqueous dimethylamine andthe solution was stirred for 1 hour. The solution was concentrated invacuo and the residue was dissolved in ethyl acetate and washed withwater. The organic layer was dried over magnesium sulfate, filtered andconcentrated to yield the crude product which was purified bycrystallization from ethyl acetate and isooctane to yield 1.80 g, (88%yield), mp.=121-122 C, HRes. MS. calc. 589.3424, found 589.3405.

EXAMPLE 12E ##STR113## Preparation of Pentanamide,2S-[[(Methylamino)acetyl]amino]N-[2R-hydroxy-3-[(3-methylbutyl)(phenylsulfonyl)amino]-1S-(phenylmethyl)propyl]-3S-methyl--

To a solution of the chloroacetamide of Example 12D, Part C, (2.36 g,4.0 mmol) in tetrahydrofuran (25 mL) was added 3 mL of aqueousmethylamine 40 wt %, and the reaction stirred for 1 hour. The contentswere concentrated and the residue was partitioned between ethyl acetate(100 mL) and water (100 mL). The organic layer was dried over magnesiumsulfate, filtered and concentrated to yield the crude product, which waspurified by recrystallization from ethyl acetate heptane; (M+H)₅₇₅.HRes.found 575.3267.

EXAMPLE 12F ##STR114## Preparation of Pentanamide,2S-[[(Dimethylamino)acetyl]amino]-N-[2R-hydroxy-3-[(3-methylpropyl)(4-methoxyphenylsulfonyl)amino]-1S-(phenylmethyl)propyl]-3S-methyl--

Part A:

To a solution of2R-hydroxy-3-[(2-methylpropyl)(4-methoxyphenylsulfonyl)amino]1-S-propylamine(1.70 g, 4.18 mmol) in 40 mL of dichloromethane was addedN-carbobenzyloxy-L-isoleucine-N-hydroxysuccinamide ester (1.51 g, 4.18mmol) and the solution stirred under nitrogen atmosphere for 16 hours.The contents were concentrated in vacuo and the residue was redissolvedin ethyl acetate. The ethyl acetate solution was washed with an aqueoussolution of 5% KHSO₄, saturated sodium bicarbonate, and saturated sodiumchloride, dried over magnesium sulfate, filtered, and concentrated toyield 2.47 g of crude product. The product was purified by silica gelchromatography using 1 2:1 hexane:ethyl acetate eluant to yield 2.3 g.(84% yield) of Pentanamide,2-[(carbobenzyloxy)amino]-N-[2-hydroxy-3-[(3-methylpropyl)(4-methoxyphenylsulfonyl)amino]-1-(phenylmethyl)propyl]-3-methyl-,[4-(R*,S*,S*,)].

Part B:

(1.18 g, 1.8 mmol) of the product from Part A was dissolved in 50 mL ofmethanol, and to this was added 250 mg of 10% Palladium on Carbon whileunder a stream of nitrogen. The suspension was hydrogenated using 50psig of hydrogen for 20 hours. The contents were purged with nitrogenand filtered through celite, and concentrated in vacuo to yield 935 mgof Pentanamide,2S-(amino)-N-[2R-hydroxy-3-[(3-methylpropyl)(4-methoxyphenylsulfonyl)amino]-1-S-(phenylmethyl)propyl]-3S-methyl-,which was used without further purification.

Part C:

(0.935 g, 1.8 mmol) of the amine from Part B was dissolved in 15 mL ofdioxane and to this was added (190 mg, 1.85 mmol) of 4-methylmorpholinefollowed by (0.315 g, 1.8 mmol) of chloroacetic anhydride. The reactionmixture was stirred under nitrogen atmosphere for 3 hours, concentratedin vacuo, and redissolved in ethyl acetate. The ethyl acetate solutionwas washed with 50 mL of 5% agueous KHSO₄, saturated NaHCO₃, andsaturated NaCl solution, dried over MgSO₄, filtered and concentrated toyield 613 mg, (68% yield) of Pentanamide,2S-[(chloroacetyl)amino]-N-[2R-hydroxy-3-[(3-methylpropyl)(4-methoxyphenylsulfonyl)amino]-1S-(phenylmethyl)propyl]-3S-methyl-,after purification by silica gel chromatography using 1:1 hexane:ethylacetate.

Part D:

To a solution of the chloroacetamide from Part C; (673 mg, 1.10 mmol) in20 mL of tetrahydrofuran was added 5 mL of 50 wt % aqueous dimethylamineand the solution was stirred for 1 hour. The reaction was concentratedand the residue was redissolved in 50 mL of ethyl acetate and washedwith 25 mL of water. The ethyl acetate layer was dried over magnesiumsulfate, filtered and concentrated to yield a crude solid which waspurified by silica gel column chromatography using an eluant of 97:3dichloromethane:methanol to provide 400 mg of Pentanamide,2S-[[Dimethylamino)acetyl]amino]-N-[2R-hydroxy-3-[(3-methylpropyl)(4-methoxyphenylsulfonyl)amino]-1S-(phenylmethyl)propyl]-3S-methyl-.

EXAMPLE 13A ##STR115## Preparation of Carbamic acid,[2R-hydroxy-3-[[(4-dimethylaminophenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-,phenylmethyl ester

To a solution of 100 mg (0.19 mmol) of carbamic acid,[2R-hydroxy-3-[[(4-fluorophenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-,phenylmethyl ester in 1 mL of pyridine was added 53 μL of triethylamineand 120 μL (p.95 mmol) of 40% aqueous dimethylamine. After heating for24 hours at 100 C, the solution was cooled, ethyl acetate added, thenwashed with 5% citric acid, saturated sodium bicarbonate, dried overmagnesium sulfate, filtered and concentrated. The resulting solid wasrecrystallized from ethyl acetate/hexane to afford 10 mg of the desiredproduct; mass spectrum m/e=540 (M+H).

EXAMPLE 13B ##STR116## Preparation of Carbamic acid,[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylopropyl)amino]-1S-(phenylmethyl)propyl]-,3-pyridylmethyl ester

Part A:

A solution of N-benzyloxycarbonyl-3S-amino-1,2-S-epoxy-4-phenylbutane(50 g, 0.168 mol) and isobutylamine (246 g, 3.24 mol) in 650 mL ofisopropyl alcohol was refluxed for 1.25 hours. The solution was cooledto room temperature, concentrated in vacuo and then poured into 1 L ofstirring hexane whereupon the product crystallized from solution, wascollected and air dried to give 57.6 g ofN-[3S-benzyloxycarbonylamino-2R-hydroxy-4-phenyl]-N-isobutylamine, mp108-109.5 C, mass spectrum m/e=371 (M+H).

Part B:

The amine from part A (1.11 g, 3.0 mmol) and triethylamine (324 mg, 3.20mmol) in 20 mL of methylene chloride was treated with 715 mg(3.46 mmol)of 4-methoxybenzenesulfonyl chloride. The solution was stirred at roomtemperature for 6 hours, concentrated, dissolved in ethyl acetate, thenwashed with 1N potassium hydrogen sulfate, saturated sodium bicarbonate,brine, dried over magnesium sulfate, filtered and concentrated to afforda clear oil. This was recrystallized from diethyl ether to afford 1.27 gof carbamic acid,[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-,phenylmethyl ester, mp 97-101 C, mass spectrum m/e=541 (M+H).

Part C:

A solution of 930 mg (3.20 mmol) of the product of part B in 30 mL ofmethanol was hydrogenated in the presence of 70 mg of a 10% palladium oncarbon catalyst under 40 psig for 17 hours, the catalyst was removed byfiltration, and the solution concentrated to afford 704 mg of[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propylamine,mass spectrum m/e=407 (M+H), which was used directly in the next stepwithout purification.

Part D:

To a solution of 2.5 g (22.9 mmol) of 3-pyridylcarbinol in 100 mL ofanhydrous acetonitrile was added 8.8 g (34.4 mmol) ofN,N'-disuccinimidyl carbonate and 5.55 mL (68.7 mmol) of pyridine. Thesolution was stirred for 1 hour and then concentrated in vacuo. Theresidue was dissolved in ethyl acetate, then washed with saturatedsodium bicarbonate, brine, dried over magnesium sulfate, filtered andconcentrated to afford 5.3 g of N-Hydroxysuccinimide-3-pyridylmethylcarbonate, mass spectrum m/e=251 (M+H), which was used directly in thenext step without purification.

Part E:

To a solution of the amine from part C (2.87 g, 7.0 mmol) and 1.38 mL oftriethylamine in 24 mL of anhydrous methylene chloride was added asolution of 1.65 g (6.6 mmol) of N-hydroxysuccinimide-3-pyridylcarbonate from part D in 24 mL of methylene chloride, The solution wasstirred for 1 hour, 100 mL of methylene chloride added, then washed withsaturated sodium bicarbonate, brine, dried over sodium sulfate, filteredand concentrated to afford 3.69 g of crude product. Chromatography onsilica gel using 2% methanol/methylene chloride to afford 3.27 g ofcarbamic acid,[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-,3-pyridylmethyl ester, mass spectrum m/e=548 (M+Li).

EXAMPLE 13C ##STR117## Preparation of Carbamic acid,[2R-hydroxy-3-[(phenylsulfonyl)(2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-,3-pyridylmethyl ester

Part A:

A solution of N-benzyloxycarbonyl-3S-amino-1,2-S-epoxy-4-phenylbutane(50 g, 0.168 mol) and isobutylamine (246 g, 3.24 mol) in 650 mL ofisopropyl alcohol was refluxed for 1.25 hours. The solution was cooledto room temperature, concentrated in vacuo and then poured into 1 L ofstirring hexane whereupon the product crystallized from solution, wascollected and air dried to give 57.6 g ofN-[3S-benzyloxycarbonylamino-2R-hydroxy-4-phenyl]-N-isobutylamine, mp108-109.5 C, mass spectrum m/e=371(M+H).

Part B:

The amine from part A (0.94 g, 2.5 mmol) and triethylamine (288 mg,2.85mmol) in 20 mL of methylene chloride was treated with 461 mg(2.61 mmol)of benzenesulfonyl chloride. The solution was stirred at roomtemperature for 16 hours, concentrated, dissolved in ethyl acetate, thenwashed with 1N potassium hydrogen sulfate, saturated sodium bicarbonate,brine, dried over magnesium sulfate, filtered and concentrated to afforda clear oil. This was recrystallized from diethyl ether and hexane toafford 0.73 g of carbamic acid,[2R-hydroxy-3-[(phenylsulfonyl)(2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-,phenylmethyl ester, mp 95-99 C, mass spectrum m/e=511 (M+H).

Part C:

A solution of 500 mg of carbamic acid,[2R-hydroxy-3-[(phenylsulfonyl)(2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-,phenylmethyl ester in 20 mL of methanol was hydrogenated in the presenceof 250 mg of a 10% palladium on carbon catalyst under 40 psig for 3hours, the catalyst was removed by filtration, and the solutionconcentrated to afford 352 mg of[2R-hydroxy-3-[(phenylsulfonyl])2-methylpropyl)amino]-1S-(phenylmethyl)propylamine,mass spectrum m/e=377 (M+H), which was used directly in the next stepwithout purification.

Part D:

To a solution of 1.24 mmol of 5-norbornene-2,3-dicarboximidocarbonochloridate (Henklein, P., et. al., Synthesis 1987, 166-167) in 1mL of anhydrous methylene chloride, was added a solution of 43 μL (2.44mmol) of 3-pyridylcarbinol and 129 4 μL (1.6 mmol) of pyridine in 1 mLof methylene chloride at 0° C. under a nitrogen atmosphere. After 4hours at room temperature, 150 mg (0.4 mmol) of[2R-hydroxy-3-[(phenylsulfonyl])2-methylpropyl)amino]-1S-(phenylmethyl)propylaminefrom Part C above was added and 100 μL of pyridine. After stirring for15 hours at room temperature, ethyl acetate was added, then washed with1N hydrochloric acid, saturated sodium bicarbonate, brine, dried overmagnesium sulfate, filtered and concentrated to afford 175 mg of crudeproduct. Chromatography over silica gel using 1% methanol/methylenechloride tp afford 69 mg of pure carbamic acid,[2R-hydroxy-3-[(phenylsulfonyl)(2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-,3-pyridylmethyl ester, mass spectrum m/e=512.2267 (M+H); calcd for C₂₇H₃₃ N₃ O₅ S, 512.2219.

EXAMPLE 13D ##STR118## Preparation of Carbamic acid,[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)-propyl]-,3-pyridylmethyl ester, N-oxide

To a solution of 211 mg (0.39 mmol) of carbamic acid,[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-,3-pyridylmethyl ester in 5 mL of methylene chloride at 0 C was added 500mg of 50% 3-chloroperbenzoic acid. After stirring at room temperaturefor 1 hour, ethyl acetate was added, the solution washed with saturatedsodium bicarbonate, 0.2N ammonium hydroxide solution and brine, driedover magnesium sulfate, filtered and concentrated to afford 200 mg ofcrude product. This was chromatographed on C18 reverse phase materialusing 20-40% acetonitrile/water, then 100% acetonitrile to afford 90 mgof the desired product, which was then recrystallized from ethylacetate/isooctane to yield 34 mg of pure carbamic acid,[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-,3-pyridylmethyl ester, N-oxide; mass spectrum m/e=564 (M+Li).

EXAMPLE 13E ##STR119## Preparation of Carbamic acid,[2R-hydroxy-3-[[(4-hydroxyphenyl)sulfonyl]-(2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-,3-pyridylmethyl ester

Part A:

A solution of 0.98 g (1.85 mmol) of carbamic acid,[2R-hydroxy-3-[[(4-fluorophenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-phenylmethylester in 3.8 mL of anhydrous DMF was added to 22 mg (7.4 mmol) of 80%sodium hydride in 2 mL of DMF. To this mixture was added 0.40 g (3.7mmol) of benzyl alcohol. After 2 hours, the solution was cooled to 0 C,water added, and then ethyl acetate. The organic layer was washed with5% cirtic acid, saturated sodium bicarbonate and brine, dried overmagnesium sulfate, filtered and concentrated to afford 0.90 g of crudematerial. This was chromatographed on basic alumina using 3%methanol/methylene chloride to afford 0.70 g of2R-hydroxy-3-[(2-methylpropyl)(4-hydroxyphenyl)sulfonyl]amino-1S-(phenylmethyl)propylamine, cyclic carbamate; mass spectrumm/e=509(M+H).

Part B:

To a solution of 0.65 g (1.28 mmol) of the cyclic carbamate from part Ain 15 mL of ethanol, was added 2.6 mL (6.4 mmol) of 2.5N sodiumhydroxide solution. After 1 hour at reflux, 4 mL of water was added andthe solution refluxed for an additional eight hours. The volatiles wereremoved, ethyl acetate added, and washed with water, brine, dried overmagnesium sulfate, filtered and concentrated to afford 550 mg ofcrude2R-hydroxy-3-[(2-methylpropyl)(4-hydroxyphenyl)sulfonyl]amino-1S-(phenylmethyl)propylamine.

Part C:

A solution of crude2R-hydroxy-3-[(2-methylpropyl)(4-benzyloxyphenyl)sulfonyl]amino-1S-(phenylmethyl)propylaminein 10 mL of ethanol was hydrogenated in the presence of 500 mg of a 10%palldium on carbon catalyst under 50 psig of hydrogen for 2 hours. Thecatalyst was removed by filtration and the solvent removed in vacuo toafford 330 mg of 2R-hydroxy-3-[(2-methylpropyl)(4-hydroxyphenyl)sulfonyl]amino-1S-(phenylmethyl)propylamine, mass spectrum m/e=393(M+H).

Part D:

To a solution of 320 mg (0.82 mmol) of the amine from part C in 6 mL ofDMF, was added 192 mg (0.76 mmol) ofN-hydroxysuccinimide-3-pyridylmethyl carbonate. After 15 hours at roomtemperature, the DMF was removed in vacuo, ethyl acetate added, washedwith water, brine, dried with magnesium sulfate, filtered andconcentrated to afford 390 mg of crude material. Chromatogrpahy onsilica gel using 50-80% ethyl acetate/hexane afforded 180 mg of carbamicacid,[2R-hydroxy-3-[[(4-hydroxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-,3-pyridylmethylester, mass spectrum m/e=528(M+H)

EXAMPLE 13F ##STR120## Preparation of Carbamic acid,[2R-hydroxy-3-[[(4-methoxy-phenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)-propyl]-,5pyrimidylmethyl ester

To a solution of 9.5 mg (0.09 mmol) of 5-pyrimidylcarbinol in 1 mL ofanhydrous acetonitrile at room temperature, was added 24 mg (0.09 mmol)of N,N'-disuccinimidyl carbonate and 19.1 μL (0.24 mmol) of pyridine.After stirring for 5 hours , 32 mg (0.08 mmol) of2R-hydroxy-3-[(2-methylpropyl)(4-methoxyphenyl)sulfonyl]amino-1S-(phenylmethyl)propylaminewas added and the solution stirred for 48 hours. After concentration invacuo, methylene chloride was added, then washed with a 1:1 mixture ofsaturated sodium bicarbonate and brine, dried over magnesium sulfate,filtered and concentrated to give 27 mg of crude product. Chromatographyon silica gel using 2% methanol/methylene chloride afforded 22 mg of thedesired product, mass spectrum m/e=543(M+H).

EXAMPLE 13G ##STR121## Preparation of Carbamic acid,[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-,3-(6-aminopyridyl)methyl ester.

Part A. Prepartion of Ethyl 6-Aminonicotinate.

To a suspension of 1.3 g(9.4 mmol) 6-aminonicotinic acid in 100 mL ofethanol, was bubbled in dry hydrochloric acid at 0 C, then the solutionwas refluxed until all the solids dissolved. The solvents were removedunder reduced pressure, the residue dissolved in ethyl acetate, washedwith saturated sodium bicarbonate, brine and concentrated to afford 1.37g of a white solid, m/e=166(M+H).

Part B. Preparation of Ethyl 6-(tert-Butyloxycarbonylamino)nicotinate.

A mixture of 848 mg(5.1 mmol) of ethyl 6-aminonicotinate from part A,1.11 g(5.1 mmol) of di-tert-butylpyrocarbonate and 0.71 mL(5.1 mmol) oftriethylamine in 10 mL of anhydrous toluene was refluxed for 15 hours.The solution was cooled, ethyl acetate added, washed with saturatedsodium bicarbonate, brine, dried over anhydrous magnesium sulfate,filtered and concentrated to afford 1.28 g of the desired ethyl6-(tert-butyloxycarbonylamino)nicotinate, m/e=267(M+H), which was useddirectly in the next step.

Part C. Preparation of 6-(tert-Butyloxycarbonylamino)-3-pyridylmethanol.

To 4.6 mL(4.6 mmol) of a 1M solution of lithium aluminum hydride indiethyl ether at -40 C under a nitrogen atmosphere, was added a solutionof 618 mg(2.3 mmol) of ethyl 6-(tert-butyloxycarbonylamino)nicotinatefrom part B in 40 mL of anhydrous tetrahydrofuran. After the addition,this was warmed to room temperature, stirred for 3 hours, cooled to 0 C,and 145 μL of water, 145 μL of 20% sodium hydroxide solution and 290 μLof water were successively added. To the resulting mixture was added 50mL of tetrahydrofuran and stirring continued for 30 minutes. Anhydrousmagnesium sulfate was added, the solids removed via filtration and thefiltrate concentrated under reduced pressure to afford 460 mg of thedesired product, m/e=224(M+), which was used directly in the next step.

Part D. Preparation of Carbamic acid,[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-,3-[(6-tert-butyloxycarbonylamino)pyridyl]methyl ester.

To a solution of 336 mg (1.5 mmol) of6-(tert-butyloxycarbonylamino)-3-pyridylmethanol from part C in 14 mL ofanhydrous acetonitrile at room temperature under a nitrogen atmosphere,was added 384 mg(1.5 mmol) of N,N'-disuccinimidyl carbonate and 364μL(4.5 mmol) of anhydrous pyridine. After 4 hours, 406 mg(1 mmol) of2R-hydroxy-3-[(2-methylpropyl)(4-methoxyphenyl)sulfonyl]amino-1S-(phenylmethyl)propylaminewas added and stirring continued for 19 hours. The solvent was removedunder reduced pressure, ethyl acetate added, washed with saturatedsodium bicarbonate, brine, dried over magnesium sulfate, filtered andconcentrated to afford 702 mg of crude product. Chromatography on silicagel using 1% methanol/methylene chloride as eluent afforded 170 mg ofthe desired carbamic acid,[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-,3-[(6-tert-butyloxycarbonylamino)pyridyl]methyl ester, m/e=663(M+Li).

Part E. Preparation of Carbamic acid,[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methyipropyl)amino]-1S-(phenylmethyl)propyl]-,3-(6-aminopyridyl)methyl ester.

To 5 mL of 4N hydrochloric acid in dioxane at room temperature, wasadded 150 mg(0.23 mmol) of carbamic acid,[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-,3-[(6-tert-butyloxycarbonylamino)pyridyl]methyl ester from part D. Afterstirring at room temperature for 28 hours, the solvent was removed underreduced pressure, the resulting solids triturated with diethyl ether,then dissolved in ethyl acetate and saturated sodium bicarbonatesolution, separated, the organic layer washed with brine, dried withmagnesium sulfate, filtered and concentrated. The residue waschromatographed on silica gel using 2.5% methanol/methylene chloride toyield 59 mg of the desired carbamic acid,[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-,3-(6-aminopyridyl)methyl ester, m/e=557(M+H).

EXAMPLE 13H ##STR122## Preparation of Carbamic acid,[2R-hydroxy-3-[[(4-hydroxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-,3-(6-aminopyridyl)methyl ester.

Part A. Preparation of Carbamic acid,[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-,3-[(6-tert-butyloxycarbonylamino)pyridyl]methyl ester.

To a solution of 505 mg (2.25 mmol) of6-(tert-butyloxycarbonylamino)-3-pyridylmethanol from in 20 mL ofanhydrous acetonitrile at room temperature under a nitrogen atmosphere,was added 576 mg(2.25 mmol) of N,N'-disuccinimidyl carbonate and 546μl(6.75 mmol) of anhydrous pyridine. After 1 hour, 837 mg(1.87 mmol) of2R-hydroxy-3-[(2-methylpropyl)(4-hydroxyphenyl)sulfonyl]amino-1S-(phenylmethyl)propylaminewas added and stirring continued for 3 hours. The solvent was removedunder reduced pressure, ethyl acetate added, washed with saturatedsodium bicarbonate, brine, dried over magnesium sulfate, filtered andconcentrated to afford 1.37 g of crude product. Chromatography on silicagel using 1% methanol/methylene chloride as eluent afforded 830 mg ofmaterial which was identified as a mixture of the desired carbamic acid,[2R-hydroxy-3-[[(4-hydroxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-,3-[(6-tert-butyloxycarbonylamino)pyridyl]methyl ester and the cycliccarbamate derived from the2R-hydroxy-3-[(2-methylpropyl)(4-hydroxyphenyl)sulfonyl]amino-1S-(phenylmethyl)propylamine.The mixture was very difficult to separate, so was used as is in thenext step.

Part B. Preparation of Carbamic acid,[2R-hydroxy-3-[[(4-hydroxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-,3-(6-aminopyridyl)methyl ester.

To 830 mg of the mixture from part A, was added 50 mL of a 1:1 mixtureof trifluoroacetic acid and methylene chloride. After 2.5 hours at roomtemperature, the solvent was removed under reduced pressure, ethylacetate added, washed with saturated sodium bicarbonate, dried overmagnesium sulfate, filtered and concentrated to afford 720 mg of crudematerial. This was chromatgraphed on silica gel using 5% methanol/ethylacetate as eluent to yield 220 mg of product, which was recrystallizedfrom methylene chloride/diethyl ether to afford 108 mg of the desiredcarbamic acid,[2R-hydroxy-3-[[(4-hydroxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-,3-(6-aminopyridyl)methyl ester, m/e=549(M+Li).

EXAMPLE 13I ##STR123## Preparation of Carbamic acid,[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]1S-(phenylmethyl)propyl]-,3-(6-hydroxypyridyl)methyl ester.

Part A. Preparation of tert-Butyldimethylsilyl6-(tert-butyldimethylsiloxy)nicotinate.

To a solution of 5.0 g(35.9 mmol) of 6-hydroxynicotinic acid in 200 mLof anhydrous N,N-dimethylformamide at room temperature, was added 8.56 g(125 mmol) of imidazole and then 13.5 g(89 mmol) oftert-butyldimethylsilyl chloride. After 20 hours, the solvent wasremoved under reduced pressure, ethyl acetate added, washed with water,5% citric acid, saturated sodium bicarbonate, brine, dried overanhydrous magnesium sulfate, filtered and concentrated to afford 10.5 gof crude material, m/e=368(M+H).

Part B. Preparation of 3-(6-tert-butyldimethylsiloxy)pyridylcarbinol.

To 11 mL of 1M solution of lithium aluminum hydride in diethyl ether at-35 C under a nitrogen atmosphere, was added a solution of 2.0 g(5.46mmol) of product from part A in 20 mL of anhydrous diethyl ether. After30 minutes, the reaction was warmed to 0 C and stirred for 40 minutes.The solution was then quenched by the careful addition of 0.42 mL ofwater, 0.42 mL of 20% sodium hydroxide solution, and 0.84 mL of ater.Ethyl acetate was added, the precipate filtered and the organic phaseconcentrated to yield 0.93 g of crude3-(6-tert-butyldimethylsiloxy)pyridylcarbinol, which was used directlyin the next step.

Part C. Preparation of Carbamic acid,[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-,3-(6-hydroxypyridyl)methyl ester.

To a solution of 860 mg(3.6 mmol) of material from part B in 15 mL ofanhydrous acetonitrile, was added 919 mg(3.6 mmol) of N,N'disuccinimidylcarbonate and 0.87 mL of pyridine. After 1 hour, 1.42 g(3.5 mmol) of2R-hydroxy-3-[(2-methylpropyl)(4-methoxyphenyl)sulfonyl]amino-1S-(phenylmethyl)propylaminewas added. After 14 hours at room temperature, the solvent was removedunder reduced pressure, the residue dissolved in ethyl acetate, washedwith 5% citric acid, saturated sodium bicarbonate, brine, dried overmagnesium sulfate, filtered and concentrated to afford 2.1 g of crudematerial. This was directly deprotected by dissolving in 40 mL of 80%acetic acid/water and stirring for 2 hours. The solvents were removedunder reduced pressure, the residue dissolved in ethyl acetate, washedwith saturated sodium bicarbonate, brine, dried over magnesium sulfate,filtered and concentrated to afford 1.7 g of crude product. This waschromatographed on silica gel using 50-100% ethyl acetate/hexane toprovide a fraction of 0.19 g of fairly pure material, which was furtherpurified by reverse phase chromatography using 15-40%acetonitrile/water(0.05% trifluoroacetic acid) to provide 120 mg of thedesired carbamic acid,[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)aminon]-1S-(phenylmethyl)propyl]-,3-(6-hydroxypyridyl)methyl ester, m/e=558(M+H)

EXAMPLE 13J ##STR124## Preparation of Carbamic acid,[2R-hydroxy-3-[[(4-hydroxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyyl],5-pyrimidylmethyl ester.

To a solution of 237 mg (2.15 mmol) of 5-pyrimidylcarbinol in 24 mL ofanhydrous acetonitrile , was added 602 mg is (2.35 mmol) ofN,N'-disuccinimidyl carbonate and then 0.47 mL of pyridine. Afterstirring for 4.5 hours, 766 mg(196 mmol) of2R-hydroxy-3-[(2-methylpropyl)(4-hydroxyphenyl)sulfonyl]amino-1-(phenylmethyl)propylamine was added. After stirring for 19 hours, the solvent was removedunder reduced pressure, ethyl acetate added, washed with 5% citric acid,saturated sodium bicarbonate, brine, dried over anhydrous magnesiumsulfate, filtered and concentrated to afford 1.0 g of crude material.Chromatography on silica gel using 50-100% ethyl acetate/hexane aseluent afforded 450 mg of the desired carbamic acid,[2R-hydroxy-3-[[(4-hydroxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-,5-pyrimidylmethyl ester, m/e=529(M+H).

EXAMPLE 14 ##STR125## Preparation ofphenylmethyl[3-amino-1S-[[2R-hydroxy-3-[(3-propyl)(phenylsulfonyl)amino]-1S-(phenylmethyl)amino]-carbonyl]-3-oxopropyl]carbamate

Phenylmethyl[2R-hydroxy-3-[(3-propyl)(phenylsulfonyl)amino]-1S-(phenylmethyl)propyl]-carbamate (200 mg, 0.40mmol) was deprotected by hydrogenation over 10% palladium on carbon andthe resulting free amine was coupled with N-CBZ-L-asparagine (157mg,0.42 mmol) in the presence of N-hydroxybenzotriazole (114 mg, 0.84mmol) and EDC (130 mg, 0.67 mmol) to give phenylmethyl[3-amino-1S-[[2R-hydroxy-3-[(3-propyl)(phenylsulfonyl)amino]-1S-(phenylmethyl)amino]carbonyl]-3-oxopropyl]carbamateas a solid. Anal. Calcd for C₃₁ H₃₈ N₄ O₇ S.0.2H₂ O: C,60.61; H,6.30;N,9.12. Found: C,60.27; H,6.16; N,8.93.

EXAMPLE 15A ##STR126##

Preparation of N1-[2R-hydroxy-3-[(3-methylbutyl)(phenyl-sulfonyl)amino]-N4-methyl-1S-(phenylmethyl)propyl]-2S-[(2-quinolinylcarbonyl)amino]butanediamide

Part A:

N2-[(1,1-dimethylethoxy)carbonyl]-N-methyl-L-asparagine was preparedfrom Boc-L-aspartic acid alpha-benzyl ester(1.0 g, 3.09 mmol),methylamine.HCl (209 mg, 3.09 mmol), EDC(711 mg, 3.7 mmol),1-hydroxybenzotriazole (627 mg, 4.63 mmol), and N-methylmorpholine (0.7mL, 6.3 mmol), in DMF (20 mL). After stirring overnight at r.t., thereaction mixture was diluted with ethyl acetate, washed with water, sat.sodium bicarbonate, 5% citric acid, brine, dried over magnesium sulfateand concentrated to an oil. The oil was taken up in 20 mL dry ethanol,and hydrogenated in the presence of 10% w/w of 10% Pd on C atatmospheric pressure and room temperature overnight. The mixture wasfiltered through Celite and concentrated to a white solid foam, 670 mg.

Part B:

A solution of phenylmethyl [2R-hydroxy-3-[(3-methylbutyl)(phenylsulfonyl)amino]-1S-(phenylmethyl)-propyl]carbamate (310 mg, 0.59mmol) in methanol (10 mL) was hydrogenated over 10% palladium on carbonfor 3 h., filtered through diatomaceous earth and concentrated to givethe product as an oil (214 mg) This free amine (208 mg, 0.53 mmol) wascoupled with N2-[(1,1-dimethylethoxy)-carbonyl]-N-methyl-L-asparagine(137 mg, 0.56 mmol) in the presence of N-hydroxybenzotriazole (102 mg,0.76 mmol) and EDC (130 mg, 0.67 mmol) to yield 290 mg ofN1[2R-hydroxy-3-[(3-methylbutyl)(phenylsulfonyl)-amino]-N4-methyl-1S-(phenylmethyl)propyl]-2S-[(1,1-dimethylethoxy-carbonyl)amino]butane diamide.

Part C:

N1[2R-hydroxy-3-[(3-methylbutyl)(phenyl-sulfonyl)amino]-N4-methyl-1S-(phenylmethyl)propyl]-2S-[(1,1-dimethylethoxycarbonyl)-amino]butanediamide(270 mg, 0.43 mmol) was stirred in 4N HCl in dioxane (5 mL) atr.t. for 0.5 h. Solvent and excess reagent were evaporated to dryness.The product was dried in vacuo. This material (125 mg, 0.225 mmol) wasthen reacted with 2-quinoline carboxylic acid N-hydroxysuccimide ester(61 mg, 0.225 mmol), N-methylmorpholine (50 uL, 0.45 mmol) in methylenechloride (2 mL) for 3 h. The product N1 [2R-hydroxy-3-[(3-methylbutyl)(phenylsulfonyl)amino]-N4-methyl-1S-(phenylmethyl)propyl]-2S-[(2-quinolinylcarbonyl)-amino]butanediamide was purified by silica gel chromatography. Anal. Calcd for C₃₆H₄₃ N₅ O₆ S.0.2H₂ O: C,63.83; H,6.45; N,10.34. Found: C,63.64; H,6.40;N,10.34.

EXAMPLE 15B

Following the procedures set forth above, the following compound wasalso prepared: ##STR127##

Preparation of Carbamic acid,[3-[[2-hydroxy-3-[(3-methylbutyl)(phenylsutonyl)amino]-1-(phenylmethyl)propyl]amino]-2-methyl-3-oxopropyl]-,(4-methoxyohenyl)methyl ester, [1S-[1R*(S*),2S*]--

Thus, 4.10 g, (7.8 mmol), of Carbamic acid,[2R-hydroxy-3-[(3-methylbutyl) (phenylsulphonyl)amino]-1S-(phenylmethyl)propyl]-, phenylmethyl ester, [R-(R*,S*)]-was hydrogenated in a solutionof methanol and ethanol using catalytic Pd/C 10% at 50 psig hydrogen for3 hours. The catalyst was filtered and the solvents removed in vacuo toyield 3.0 grams of free amine.

In a separate flask, 2.09 g, (7.8 mmol), of N-Moz-AMBA was added to 10mL of dimethylformamide and 1.58 g, (1.5 equiv.), ofN-hydroxybenzoltriazole and the solution was cooled to 5 degrees C. Tothis solution was added 1.49 g, (7.8 mmol), of EDC and the solutionstirred for 30 min. To this was added the free amine in 10 mL ofdimethylformamide, and the reaction was stirred for 20 hours. Thesolvent was removed by evaporation and the crude material waspartitioned between ethyl acetate and saturated aqueous sodiumbicarbonate. The ethyl acetate layer was washed with 5% potassiumhydrogen sulfate and brine, dried over magnesium sulfate, filtered andconcentrated to yield 2.58 grams of pure product after recrystallizationfrom ethyl acetate, ether, and hexanes. 52% yield.

EXAMPLE 16A ##STR128## Preparation of Carbamic acid,[2R-hydroxy-3-[(4-methoxyyhenylsulfonyl)(2-methylpronyl)amino]-1S-(phenylmethyl)propyl-,3-S-tetrahydrofuran-3-yl-ester

To a solution of 406 mg (1.0 mmol) of[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propylamine in 5.0 mL of dichloromethane containing 150 mg(1.Smmol) oftriethylamine was added 280 mg (1.22 mmol) ofN-succinimidyl-3-(S)-tetrahydrofuranyl carbonate and the reacton mixturewas stirred for 2 hours, an additional 136 mg (0.3 mmol) of amine wasadded to the mixture and the solution stirred another 2 hours. Thecontents were diluted with 50 mL of ethyl acetate and washed with 5%aqueous citric acid, saturated sodium bicarbonate, and brine, then driedover magnesium sulfate, filtered and concentrated to yield 330 mg ofcrude product. Purification by silica gel chromatography using an eluantof 1:1 to 2:1 ethyl acetate/hexanes gradient provided Carbamic acid,[2R-hydroxy-3-[(4-methoxyphenylsulfonyl) (2-methylpropyl)amino]-1S-(phenylmethyl)propyl-, 3-S-tetrahydrofuran-3-yl-ester as awhite solid. m/z=521 (M+H) calc. 521.2311 obs. 521.2311.

EXAMPLE 16B ##STR129## Preparation of Carbamic acid,[2R-hydroxy-3-[(4-hydroxyphenylsulfonyl)(2-methylpropyl)amino]-1S-(phenylmethyl)propyl-,3-S-tetrahydrofuran-3-yl-ester

To a solution of 435 mg (1.0 mmol) of[2R-hydroxy-3-[[(4-hydroxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propylamine in 3.0 mL of dimethylformamide was added 225 mg (0.98 mmol)of N-succinimidyl-3-(S)-tetrahydrofuranyl carbonate and the solution wasstirred overnight. The mixture was diluted with 50 mL of ethyl acetateand washed with 5% aqueous citric acid, saturated sodium bicarbonate,and brine, dried over magnesium sulfate, filtered and concentrated toyield 515 mg of crude product. Purificaton by silica gel chromatographyusing and eluant of 1:1 ethyl acetate :hexanes provided 315 mg ofCarbamic acid, [2R-hydroxy-3-[(4-hydroxyphenylsulfonyl)(2-methylpropyl)amino]-1S-(phenylmethyl)propyl-,3-S-tetrahydrofuran-3-yl-ester, as a white solid. m.p=HRMS calc.507.2165, obs. 507.2155.

EXAMPLE 16C ##STR130## Preparation of Carbamic acid,[2R-hydroxy-3-[(4-methoxyyphenylsulfonyl)(2-methylpronyl)amino]-1S-(phenylmethyl)propyl-,3-S-tetrahydrothiophen-3-yl-ester

To a solution of 215 mg (2.0 mmol) of 3-S-hydroxythiophene, 415 μL ofanhydrous pyridine,and 2 mL of dry acetonitrile was added 512 mg (2.0mmol) of N,N'-Dimethylsuccinimidyl carbonate and this suspension wasstirred for 45 minutes. To this clear solution was added a solution of700 mg (1.7 mmol) of[2R-hydroxy-3-[[(4-methoxyyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propylaminein 2.0 mL of acetonitrile and stirred for 12 hours. the contents wereconcentrated, and the residue was partitioned between ethyl acetate and5% aqueous potassium hydrogen sulfate. The organic layer was washed withsaturated sodium bicarbonate and then brine, dried over sodium sulfate,filtered and concentrated to yield 780 mg of crude material. Purificatonby silica gel chromatograpy using an eluant of 10:10:1 ethyl acetate:hexane:methanol provided 520 mg of Carbamic acid,[2R-hydroxy-3-[(4-methoxyphenylsulfonyl)(2-methylpropyl)amino]-1S-(phenylmethyl)propyl-,3-S-tetrahydrothiophen-3-yl-ester, as a crystalline white solid.m.p.=162-3° C., m/z=553 (M+H).

EXAMPLE 16D ##STR131##

Preparation of Carbamic acid, [2R-hydroxy-3-[(4-methoxyphenylsulfonyl)(2-methylpropyl)amino]-1S-(phenylmethyl)propyl-,3(S)-1,1-dioxotetrahydrothiophen-3-yl-ester

To a solution of 270 mg (0.5 mmol) of Carbamic acid,[2R-hydroxy-3-[(4-methoxyphenylsulfonyl)(2-methylpropyl)amino]-1S-(phenylmethyl)propyl-,3-S-tetrahydrothiophen-3-yl-ester in 30 mL of dichloromethane was added400 mg (1.2 mmol) of m-chloroperbenzoic acid (50 wt %) and the mixturewas stirred for 12 hours. The contents were diluted with 10 mL of 10%aqueous sodium metabisulfite and stirred for 30 minutes. The organiclayer was washed with saturated sodium bicarbonate, dried over sodiumsulfate, filtered and concentrated to yield 290 mg of crude product.Purification by silica gel chromatography using an eluant of 10:10:1ethyl acetate:hexane:methanol provided 260 mg of Carbamic acid,[2R-hydroxy-3-[(4-methoxyphenylsulfonyl)(2-methylpropyl)amino]-1S-(phenylmethyl)propyl-,3(S)-1,1-dioxotetrahydrothiophen-3-yl-ester, as a white crystallinesolid. m.p.=69° C., m/z=569 (M+H).

EXAMPLE 16E ##STR132## Preparation of Carbamic acid,[2R-hydroxy-3-[(4-hydroxythenylsulfonyl)(2-methylpropyl)amino]-1S-(phenylmethyl)propyl-,3-S-tetrahydrothiophen-3-yl-ester

To a solution of 125 mg (1.2 mmol) of 3-S-hydroxythiophene, 250 μL ofanhydrous pyridine,and 1 mL of dry acetonitrile was added 307 mg (1.2mmol) of N,N'-Dimethylsuccinimidyl carbonate and this suspension wasstirred for 45 minutes. To this clear solution was added a solution of445 mg (1.0 mmol)[2R-hydroxy-3-[[(4-hydroxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propylamine in 1.0 mL of acetonitrile and stirred for 12 hours. thecontents were concentrated, and the residue was partitioned betweenethyl acetate and 5% aqueous potassium hydrogen sulfate. The organiclayer was washed with saturated sodium bicarbonate and then brine, driedover sodium sulfate, filtered and concentrated to yield 460 mg of crudematerial. Purificaton by silica gel chromatograpy using an eluant of10:10:1 ethyl acetate: hexane:methanol provided 235 mg of Carbamic acid,[2R-hydroxy-3-[(4-hydroxyphenylsulfonyl)(2-methylpropyl)amino]-1S-(phenylmethyl)propyl-,3-S-tetrahydrothiophen-3-yl-ester, as a crystalline white solid.m.p.=184-85° C., m/z=529 (M+Li).

EXAMPLE 16F ##STR133## Preparation of Carbamic acid,[2R-hydroxy-3-[(4-hydroxyphenylsulfonyl)(2-methyl-ronyl)amino]-1S-(phenylmethyl)propyl-,3(S)-1,1-dioxotetrahydrothionhen-3-yl-ester

To a solution of 125 mg (0.24 mmol) of Carbamic acid,[2R-hydroxy-3-[(4-hydroxyphenylsulfonyl)(2-methylpropyl)amino]-1S-(phenylmethyl)propyl-,3-S-tetrahydrothiophen-3-yl-ester in 30 mL of dichloromethane was added240 mg (0.7 mmol) of m-chloroperbenzoic acid (50 wt %) and the mixturewas stirred for 12 hours. The contents were diluted with 5 mL of 10%aqueous sodium metabisulfite and stirred for 30 minutes. The organiclayer was washed with saturated sodium bicarbonate, dried over sodiumsulfate, filtered and concentrated to yield 110 mg of crude product.Purification by silica gel chromatography using an eluant of 1:1 to 2:1ethyl acetate:hexane:methanol provided 100 mg of Carbamic acid,[2R-hydroxy-3-[(4-hydroxyphenylsulfonyl)(2-methylpropyl)amino]-1S-(phenylmethyl)propyl-,3(S)-1,1-dioxotetrahydrothiophen-3-yl-ester, as a white crustallinesolid, m.p.=190-1° C., m/z=561 (M+Li).

EXAMPLE 17A Carbamic acid,[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](methylpropyl)amino]-1S-(phenylmethyl)propyl]-,5-(thiazolyl)methylester can be prepared according to the following procedures. ##STR134##

To a solution of 172 mg (1.5 mmol) of 5-hydroxymethylthiazole in 14 mLof anhydrous acetonitrile at room temperatures under a nitrogenatmosphere, is added 384 mg (1.5 mmol) of N,N'-disuccinimidyl carbonateand 364 μL (4.5 mmol) of anhydrous pyridine. After about 4 hourse, 406mg (1 mmol) of 2R-hydroxy-3-[(2-methylpropyl)(4-methoxyphenyl)sulfonyl]amino-1S-(phenylmethyl)propylamine is addedand stirring would be continued for approximately 19 hours. The solventwould be removed under reduced pressure, ethyl acetate added, washedwith saturated sodium bicarbonate, brine, dried over magnesium sulfate,filtered and concentrated to afford crude product. The desired carbamicacid,[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-,5-(thiazolyl)methylester could be isolated in pure form through chromatography on silicagel using 50-100% ethyl acetate/hexane as eluent.

EXAMPLE 17B Carbamic acid,[2R-hydroxy-3-[[(4-hydroxyphenyl)sulfonyl](methylpropyl)amino]-1S-(phenylmethyl)propyl]-,5-(thiazolyl)methyl ester can be prepared according to thefollowing procedure ##STR135##

To a solution of 482 mg (4.3 mmol) of 5-(hydroxymethyl)thiazole in 48 mLof anhydrous acetonitrile, is added 1.2 g (4.7 mmol) ofN,N'-disuccinimidyl carbonate and then 0.94 mL of pyridine. Afterstirring for about 4 to 5 hours, 1.53 g (3.92 mmol) of2R-hydroxy-3-[(2-methylpropyl)(4-hydroxyphenyl)sulfonyl]amino-1S-(phenylmethyl)propylamine is added.After stirring for approximately 19 hours, the solvent would be removedunder reduced pressure, theyl acetate added, washed with 5% citric acid,saturated sodium bicarbonate, brine, dried over anhydrous magnesiumsulfate, filtered and concentrated to afford crude product. The desiredcarbamic acid,[2R-hydroxy-3-[[(4-hydroxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)pro,5-(thiazolyl)methylester could be isolated in pure form through chromatography on silicagel using 50-100% ethyl acetate/hexane as eluent.

EXAMPLE 18

Following the procedures of Examples 1-16, the compounds shown in Tables3, 5A and 5B were prepared and in Tables 4 through 17 can be prepared.

                  TABLE 3                                                         ______________________________________                                          #STR136##                                                                     Entry                                                                         No. R R.sup.1 R.sup.3 R.sup.4                                               ______________________________________                                        1    Cbz           t-Butyl    i-Amyl Methyl                                     2 N,N-Dimethylglycine t-Butyl i-Amyl Methyl                                   3 Cbz i-Propyl i-Amyl Phenyl                                                  4 Cbz sec-Butyl i-Amyl Phenyl                                                 5 Cbz CH.sub.2 C(O)NH.sub.2 n-Propyl Phenyl                                   6 N-Methylglycine t-Butyl i-Amyl Phenyl                                       7 Cbz t-Butyl i-Butyl Phenyl                                                  8 N,N-Dimethylglycine t-Butyl i-Amyl Phenyl                                   9 N-Methylglycine t-Butyl i-Amyl Phenyl                                       10 N,N-Dimethylglycine t-Butyl i-Butyl (4-OCH.sub.3)                              Phenyl                                                                    11 N-Methylglycine t-Butyl i-Butyl (4-OCH.sub.3)                                  Phenyl                                                                  ______________________________________                                    

                                      TABLE 4                                     __________________________________________________________________________      #STR137##                                                                      -                                                                          Entry No.                                                                          R             R.sup.3         R.sup.4                                    __________________________________________________________________________    1    Cbz.sup.a     CH.sub.3        n-Butyl                                      2 Cbz i-Butyl CH.sub.3                                                        3 Cbz i-Butyl n-Butyl                                                         4 Q.sup.b i-Butyl n-Butyl                                                     5 Cbz i-Propyl n-Butyl                                                        6 Q i-Propyl n-Butyl                                                          7 Cbz C.sub.6 H.sub.5 n-Butyl                                                  - 8 Cbz                                                                                                         n-Butyl #                                   - 9 Cbz                                                                                                         n-Butyl #                                   - 10 Q                                                                                                          n-Butyl #                                   - 11 Cbz                                                                                                        n-Butyl #                                  12 Cbz i-Butyl n-Propyl                                                       13 Cbz i-Butyl --CH.sub.2 CH(CH.sub.3).sub.2                                   - 14 Cbz                                                                                                        n-Butyl #                                   - 15 Cbz                                                                                                        i-Propyl                                    - 16 Cbz                                                                                                        --CH.sub.2 CH.sub.2 CH(CH.sub.3).sub.                                       2                                             - 17 Cbz i-Butyl --CH.sub.2 CH.sub.3                                         18 Cbz i-Butyl --CH(CH.sub.3).sub.2                                            - 19 Cbz i-Butyl                                                                                                #STR145##                                   - 20 Q                                                                      Butyl                                                                                                             #STR146##                                   - 21 Cbz                                                                                                        --(CH.sub.2).sub.2 CH(CH.sub.3).sub.2       - 22 Cbz (CH.sub.2).sub.2 CH(CH.sub.3).sub.2 --CH(CH.sub.3).sub.2                                              23 Q i-Butyl --CH(CH.sub.3).sub.2                                             24 Cbz i-Butyl --C(CH.sub.3).sub.3                                            25 Q i-Butyl --C(CH.sub.3).sub.3                                               - 26 Cbz                                                                      --C(CH.sub.3).sub.3                         - 27 Q                                                                                                          --C(CH.sub.3).sub.3                        28 Cbz --(CH.sub.2).sub.2 CH(CH.sub.3).sub.2 --C(CH.sub.3).sub.3                                                29 Q --(CH.sub.2).sub.2 CH(CH.sub.3).s                                       ub.2 --C(CH.sub.3).sub.3                     30 Cbz --CH.sub.2 C6H.sub.5 --C(CH.sub.3).sub.3                               31 Q --CH.sub.2 C.sub.6 H.sub.5 --C(CH.sub.3).sub.3                           32 Cbz --(CH.sub.2).sub.2 C.sub.6 H.sub.5 --C(CH.sub.3).sub.3                 33 Cbz --(CH.sub.2).sub.2 C.sub.6 H.sub.5 --C(CH.sub.3).sub.3                 34 Cbz n-Butyl --C(CH.sub.3).sub.3                                            35 Cbz n-Pentyl --C(CH.sub.3).sub.3                                           36 Cbz n-Hexyl --C(CH.sub.3).sub.3                                             - 37 Cbz                                                                                                        --C(CH.sub.3).sub.3                         - 38 Cbz --CH.sub.2 C(CH.sub.3).sub.3 --C(CH.sub.3).sub.3                    39 Q --CH.sub.2 C(CH.sub.3).sub.3 --C(CH.sub.3).sub.3                          - 40 Cbz                                                                                                        --C(CH.sub.3).sub.3                         - 41 Cbz --CH.sub.2 C.sub.6 H.sub.5 OCH.sub.3 (para) --C(CH.sub.3).sub.                                       3                                             - 42 Cbz                                                                                                        --C(CH.sub.3).sub.3                         - 43 Cbz                                                                                                        --C(CH.sub.3).sub.3                         - 44 Cbz --(CH.sub.2).sub.2 C(CH.sub.3).sub.3 --C(CH.sub.3).sub.3                                              45 Q --(CH.sub.2).sub.2 C(CH.sub.3).su                                       b.3 --C(CH.sub.3).sub.3                      46 Cbz --(CH.sub.2).sub.4 OH --C(CH.sub.3).sub.3                              47 Q --(CH.sub.2).sub.4 OH --C(CH.sub.3).sub.3                                 - 48 Q                                                                                                          --C(CH.sub.3).sub.3                         - 49 Q                                                                                                          --C(CH.sub.3).sub.3                         - 50 Cbz --CH.sub.2 CH(CH.sub.3).sub.2 --C.sub.6 H.sub.5                      - 51                                                                                                            --CH.sub.2 CH(CH.sub.3).sub.2                                               --C.sub.6 H.sub.5                             - 52                                                                                                            --CH.sub.2 CH(CH.sub.3).sub.2                                               --C.sub.6 H.sub.5                             - 53                                                                                                            --CH.sub.2 CH(CH.sub.3).sub.2                                               --C.sub.6 H.sub.5                             - 54                                                                                                            --CH.sub.2 CH(CH.sub.3).sub.2                                               --C.sub.6 H.sub.5                             - 55                                                                                                            --CH.sub.2 CH(CH.sub.3).sub.2                                               --C.sub.6 H.sub.5                             - 56                                                                                                            --CH.sub.2 CH(CH.sub.3).sub.2                                               --C.sub.6 H.sub.5                             - 57                                                                                                            --CH.sub.2 CH(CH.sub.3).sub.2                                               --C.sub.6 H.sub.5                             - 58                                                                                                            --CH.sub.2 CH(CH.sub.3).sub.2                                               --C.sub.6 H.sub.5                             - 59                                                                                                            --CH.sub.2 CH(CH.sub.3).sub.2                                               --C.sub.6 H.sub.5                             - 60                                                                                                            --CH.sub.2 CH(CH.sub.3).sub.2                                               --C.sub.6 H.sub.5                             - 61                                                                                                            --CH.sub.2 CH(CH.sub.3).sub.2                                               --C.sub.6 H.sub.5                             - 62                                                                                                            --CH.sub.2 CH(CH.sub.3).sub.2                                               --C.sub.6 H.sub.5                             - 63                                                                                                            --CH.sub.2 CH(CH.sub.3).sub.2                                               --C.sub.6 H.sub.5                             - 64                                                                                                            --CH.sub.2 CH(CH.sub.3).sub.2                                               --C.sub.6 H.sub.5                             - 65                                                                                                            --CH.sub.2 CH(CH.sub.3).sub.2                                               --C.sub.6 H.sub.5                             - 66                                                                                                            --CH.sub.2 CH(CH.sub.3).sub.2                                               --C.sub.6 H.sub.5                             - 67                                                                                                            --CH.sub.2 CH(CH.sub.3).sub.2                                               --C.sub.6 H.sub.5                             - 68                                                                                                            --CH.sub.2 CH(CH.sub.3).sub.2                                               --C.sub.6 H.sub.5                             - 69                                                                                                            --CH.sub.2 CH(CH.sub.3).sub.2                                               --C.sub.6 H.sub.5                             - 70 Q --CH.sub.2 Ph --Ph                                                     - 71 Q                                                                                                          --Ph 75##                                   - 72 Q                                                                                                          --Ph 76##                                   - 73 Q                                                                                                          --Ph 77##                                   - 74 Q                                                                                                          --Ph 78##                                   - 75 Q                                                                                                          --Ph 79##                                   - 76 Q --CH.sub.2 CH═CH.sub.2 --Ph                                        - 77 Q                                                                                                          --Ph 80##                                   - 78 Q                                                                                                          --Ph 81##                                   - 79 Q --CH.sub.2 CH.sub.2 Ph --Ph                                           80 Q --CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 OH --Ph                            81 Q --CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2 --Ph                                - 82 Q                                                                                                          --Ph 82##                                   - 83 Q --CH.sub.3 --Ph                                                       84 Q --CH.sub.2 CH.sub.2 CH.sub.2 SCH.sub.3 --Ph                              85 Q --CH.sub.2 CH.sub.2 CH.sub.2 S(O).sub.2 CH.sub.3 --Ph                     - 86 Q --CH.sub.2 CH.sub.2 CH.sub.2 CH(CH.sub.3).sub.2                                                          #STR183##                                   - 87 Q --CH.sub.2 CH.sub.2 CH(CH.sub.3).sub.2                                                                   #STR184##                                   - 88 Q --CH.sub.2 CH.sub.2 CH(CH.sub.3).sub.2 --CH.sub.2 CH.sub.2                                             CH.sub.3                                     89 Q --CH.sub.2 CH.sub.2 CH.sub.2 CH(CH.sub.3).sub.2 --CH.sub.3                                                  - 90 Q --CH.sub.2 CH.sub.2 CH(CH.sub.                                       3).sub.2                                                                        #STR185##                                   - 91 Q --CH.sub.2 CH.sub.2 CH(CH.sub.3).sub.2                                                                   #STR186##                                   - 92 Q --CH.sub.2 CH.sub.2 CH(CH.sub.3).sub.2                                                                   #STR187##                                   - 93 Q --CH.sub.2 CH.sub.2 CH(CH.sub.3).sub.2                                                                   #STR188##                                   - 94 Q --CH.sub.2 CH.sub.2 CH(CH.sub.3).sub.2                                                                   #STR189##                                   - 95 Q --CH.sub.2 CH.sub.2 CH(CH.sub.3).sub.2                                                                   #STR190##                                   - 96 Q --CH.sub.2 CH.sub.2 CH(CH.sub.3).sub.2                                                                   #STR191##                                   - 97 Q --CH.sub.2 CH.sub.2 CH(CH.sub.3).sub.2                                                                   #STR192##                                   - 98 Q --CH.sub.2 CH.sub.2 CH(CH.sub.3).sub.2                                                                   #STR193##                                   - 99 Q --CH.sub.2 CH.sub.2 CH(CH.sub.3).sub.2                                                                   #STR194##                                   - 100 Q --CH.sub.2 CH.sub.2 CH(CH.sub.3).sub.2                                                                  #STR195##                                   - 101 Q --CH.sub.2 CH.sub.2 CH(CH.sub.3).sub.2                                                                  #STR196##                                   - 102 Q --CH.sub.2 CH.sub.2 CH(CH.sub.3).sub.2                                                                  #STR197##                                   - 103 Q --CH.sub.2 CH(CH.sub.3).sub.2                                                                           #STR198##                                   - 104 Q --CH.sub.2 CH(CH.sub.3).sub.2                                                                           #STR199##                                   - 105 Q --CH.sub.2 CH(CH.sub.3).sub.2                                                                           #STR200##                                   - 106 Q --CH.sub.2 CH.sub.2 CH.sub.3                                                                            #STR201##                                   - 107 Q --CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                                  ##STR202##                                __________________________________________________________________________     .sup.a benzyloxycarbonyl                                                      .sup.b 2quinolinylcarbonyl                                               

                                      TABLE 5                                     __________________________________________________________________________      #STR203##                                                                      -                                                                          Entry                                                                            A                R.sup.3       R.sup.4                                     __________________________________________________________________________     1 Cbz-Val          i-amyl        --C.sub.6 H.sub.5                           amyl --C.sub.6 H.sub.5                                                        amyl --C.sub.6 H.sub.5                                                        Phe i-Bu methyl                                                                  -  5 Qui-Orn(g-Cbz)                                                         ## TR204##                                                                      --C.sub.6 H.sub.5                                                             -  6 Cbz-Asn --CH.sub.2 CH═CH.sub.2 --C.sub.6 H.sub.5                  amyl --C.sub.6 H.sub.5                                                        amyl --C.sub.6 H.sub.5                                                        amyl --C.sub.6 H.sub.5                                                          10 Acetyl-Leu i-amyl --C.sub.6 H.sub.5                                        11 Acetyl-His i-amyl --C.sub.6 H.sub.5                                        12 Acetyl-Thr i-amyl --C.sub.6 H.sub.5                                        13 Acetyl-NHCH(C(CH.sub.3).sub.2 (SCH.sub.3))C(O)-- i-amyl --C.sub.6        H.sub.5                                                                         14 Cbz-Asn i-amyl --C.sub.6 H.sub.5                                           15 Cbz-Ala i-amyl --C.sub.6 H.sub.5                                           16 (N,N-dimethylglycinyl)Val i-amyl --C.sub.6 H.sub.5                         17 (N-methylglycinyl)Val i-amyl --C.sub.6 H.sub.5                             18 (N,N-dimethylglycinyl)Ile i-amyl --C.sub.6 H.sub.5                         19 (N-methylglycinyl)Ile i-amyl --C.sub.6 H.sub.5                             20 Cbz-Ala i-amyl --C.sub.6 H.sub.5                                           21 Cbz-beta-cyanoAla i-amyl --C.sub.6 H.sub.5                                 22 Cbz-t-BuGly i-amyl --C.sub.6 H.sub.5                                       23 Q-t-BuGly i-amyl --C.sub.6 H.sub.5                                         24 Q-SCH.sub.3 Cys i-amyl --C.sub.6 H.sub.5                                   25 Cbz-SCH.sub.3 Cys i-amyl --C.sub.6 H.sub.5                                 26 Q-Asp i-amyl --C.sub.6 H.sub.5                                             27 Cbz-(NHCH(C(CH.sub.3).sub.2 (SCH.sub.3))C(O)-- i-amyl --C.sub.6          H.sub.5                                                                         28 Cbz-EtGly i-amyl --C.sub.6 H.sub.5                                         29 Cbz-PrGly i-amyl --C.sub.6 H.sub.5                                         30 Cbz-Thr i-amyl --C.sub.6 H.sub.5                                           31 Q-Phe i-amyl --C.sub.6 H.sub.5                                             32 Cbz-Phe i-amyl --C.sub.6 H.sub.5                                            - 33                                                                        ## i-Butyl --C.sub.6 H.sub.4                                                                                        ##STR206##                             __________________________________________________________________________

                                      TABLE 5A                                    __________________________________________________________________________      #STR207##                                                                                                                MASS MEASUREMENT                                                                      CALC                       Entry R.sup.3 R.sup.4 R.sup.7 MOL FORM M + H FOUND                          __________________________________________________________________________       1                                                                                                                                      #STR208##                                                                     #STR209##                                                                     C.sub.27                                                                    H.sub.38                                                                      N.sub.2 O.sub.5                                                               S 503.2661                                                                    503.2624                                                                        -  2                                                                          C.sub.28                                                                    H.sub.40                                                                      N.sub.2 O.sub.5                                                               S 517.2736                                                                    517.2777                                                                        -  3                                                                          C.sub.29                                                                    H.sub.42                                                                      N.sub.2 O.sub.5                                                               S 531.2893                                                                    531.2916                                                                        -  4                                                                          C.sub.32                                                                    H.sub.40                                                                      N.sub.2 O.sub.5                                                               S 565.2736                                                                    565.2731                                                                        -  5                                                                          C.sub.30                                                                    H.sub.35                                                                      N.sub.3 O.sub.5                                                               S 550.2376                                                                    550.2427                                                                        -  6                                                                          #STR215##                                                                     #STR216##                                                                     C.sub.30                                                                    H.sub.38                                                                      N.sub.2 O.sub.5                                                               S 539  (M + H)                                                                539                    -  7                                                                                                                                   C.sub.29                                                                    H.sub.36                                                                      N.sub.2 O.sub.5                                                               S ? ?                  -  8    C.sub.30 H.sub.38 N.sub.2 O.sub.5 S 539.2580  (M + H) 539.2591        -  9                                                                                                                                   #STR219##                                                                     #STR220##                                                                     C.sub.27                                                                    H.sub.33                                                                      N.sub.3 O.sub.5                                                               S 512.2219                                                                    512.2271                                                                        - 10                                                                          C.sub.28                                                                    H.sub.35                                                                      N.sub.3 O.sub.5                                                               S 526.2376                                                                    526.2388                                                                        - 11                                                                          C.sub.27                                                                    H.sub.33                                                                      N.sub.3 O.sub.5                                                               S 512.2219                                                                    512.2287                                                                        - 12                                                                          C.sub.28                                                                    H.sub.33                                                                      N.sub.2 O.sub.5                                                               ClS 545.1877                                                                  545.1887                                                                        - 13                                                                          C.sub.30                                                                    H.sub.38                                                                      N.sub.2 O.sub.5                                                               S 539.2580                                                                    539.2592                                                                        - 14                                                                          C.sub.31                                                                    H.sub.40                                                                      N.sub.2 O.sub.5                                                               S 553.2736                                                                    553.2714                                                                        - 15                                                                          C.sub.30                                                                    H.sub.38                                                                      N.sub.2 O.sub.5                                                               S 539.2580                                                                    539.2632                                                                        - 16                                                                          C.sub.30                                                                    H.sub.38                                                                      N.sub.2 O.sub.5                                                               S 539  (M + H)                                                                539                    - 17                                                                                                                                   #STR229##                                                                     #STR230##                                                                     C.sub.29                                                                    H.sub.36                                                                      N.sub.2 O.sub.7                                                               S.sub.2                                                                       589.2042  (M +                                                                H) 589.2086                                                                     - 18                                                                          C.sub.29                                                                    H.sub.36                                                                      N.sub.2 O.sub.7                                                               S.sub.2                                                                       595.2124  (M +                                                                Li) 595.2103                                                                    - 19                                                                          C.sub.29                                                                    H.sub.36                                                                      N.sub.2 O.sub.7                                                               S.sub.2                                                                       595.2124  (M +                                                                Li) 595.2191                                                                    - 20                                                                          C.sub.30                                                                    H.sub.38                                                                      N.sub.2 O.sub.7                                                               S.sub.2                                                                       609.2281  (M +                                                                Li) 609.2313                                                                    - 21                                                                          C.sub.30                                                                    H.sub.38                                                                      N.sub.2 O.sub.7                                                               S.sub.2                                                                       603.2199  (M +                                                                H) 603.2247                                                                     - 22                                                                          C.sub.30                                                                    H.sub.38                                                                      N.sub.2 O.sub.7                                                               S.sub.2                                                                       603.2199  (M +                                                                H) 603.2266                                                                     - 23                                                                          #STR237##                                                                     #STR238##                                                                     #STR239##            - 24                                                                                                                                   #STR240##                                                                     #STR241##                                                                     C.sub.27                                                                    H.sub.32                                                                      N.sub.2 O.sub.4                                                               S 481.2161                                                                    481.2213                                                                        - 25                                                                          #STR243##                                                                     #STR244##                                                                     C.sub.28                                                                    H.sub.35                                                                      N.sub.2 O.sub.5                                                               S 511.2267                                                                    511.2319                                                                        - 26                                                                          #STR246##                                                                     #STR247##                                                                     C.sub.29                                                                    H.sub.36                                                                      N.sub.2 O.sub.5                                                               S 525.2423                                                                    525.2469                                                                        - 27                                                                          C.sub.29                                                                    H.sub.36                                                                      N.sub.2 O.sub.5                                                               S 525.2428                                                                    525.2464                                                                        - 28                                                                          C.sub.29                                                                    H.sub.36                                                                      N.sub.2 O.sub.5                                                               S 525.2423                                                                    525.2432                                                                        - 29                                                                          C.sub.29                                                                    H.sub.36                                                                      N.sub.2 O.sub.6                                                               S 541.2372                                                                    541.2332                                                                        - 30                                                                          C.sub.29                                                                    H.sub.36                                                                      N.sub.2 O.sub.6                                                               S 541.2372                                                                    541.2355                                                                        - 31                                                                          C.sub.29                                                                    H.sub.36                                                                      N.sub.2 O.sub.6                                                               S 541.2372                                                                    541.2329            __________________________________________________________________________

                                      TABLE 5B                                    __________________________________________________________________________      #STR254##                                                                      -                                                                                                Molecular                                                                              Mass                                             Entry A Formula Spectrum                                                    __________________________________________________________________________                                     CSTR255##                                                                   .sub.29 H.sub.35 N.sub.3 O.sub.7 S 576 (M                                     + Li)                                             -                                                                                                           C.sub.29 H.sub.37 N.sub.3 O.sub.5 S 540                                     (M + H)                                           -                                                                                                           C.sub.31 H.sub.41 N.sub.3 O.sub.5 S 568                                     (M + H)                                           -                                                                                                           C.sub.29 H.sub.35 N.sub.3 O.sub.7 S 570                                     (M + H)                                           -                                                                                                           C.sub.29 H.sub.37 N.sub.3 O.sub.5 S 540                                     (M + H)                                           -                                                                                                           C.sub.31 H.sub.41 N.sub.3 O.sub.5 S 568                                     (M + H)                                           -                                                                                                           C.sub.29 H.sub.35 N.sub.3 O.sub.7 S 570                                     (M + H)                                           -                                                                                                           C.sub.29 H.sub.37 N.sub.3 O.sub.5 S 546                                     (M + Li)                                          -                                                                                                           C.sub.31 H.sub.41 N.sub.3 O.sub.5 S 574                                     (M + Li)                                       __________________________________________________________________________

                  TABLE 6                                                         ______________________________________                                          #STR264##                                                                     Entry               R.sup.1                                                 ______________________________________                                        1                 CH.sub.2 SO.sub.2 CH.sub.3                                    2 (R)--CH(OH)CH.sub.3                                                         3 CH(CH.sub.3).sub.2                                                          4 (R,S)CH.sub.2 SOCH.sub.3                                                    5 CH.sub.2 SO.sub.2 NH.sub.2                                                  6 CH.sub.2 SCH.sub.3                                                          7 CH.sub.2 CH(CH.sub.3).sub.2                                                 8 CH.sub.2 CH.sub.2 C(O)NH.sub.2                                              9 (S)--CH(OH)CH.sub.3                                                         10 --CH.sub.2 C.tbd.C--H                                                    ______________________________________                                    

                  TABLE 7                                                         ______________________________________                                          #STR265##                                                                     Entry       R.sup.2        A                                                ______________________________________                                        1         n-Bu           Cbz-Asn                                                2 cyclohexylmethyl Cbz-Asn                                                    3 n-Bu Boc                                                                    4 n-Bu Cbz                                                                    5 C.sub.6 H.sub.5 CH.sub.2 Boc                                                6 P-F-C.sub.6 H.sub.5 CH.sub.2 Cbz                                            7 C.sub.6 H.sub.5 CH.sub.2 benzoyl                                            8 cyclohexylmethyl Cbz                                                        9 n-Bu Q-Asn                                                                  10 cyclohexylmethyl Q-Asn                                                     11 C.sub.6 H.sub.5 CH.sub.2 Cbz-Ile                                           12 C.sub.6 H.sub.5 CH.sub.2 Q-Ile                                             13 P-F-C.sub.6 H.sub.5 CH.sub.2 Cbz-t-BuGly                                   14 C.sub.6 H.sub.5 CH.sub.2 Q-t-BuGly                                         15 C.sub.6 H.sub.5 CH.sub.2 Cbz-Val                                           16 C.sub.6 H.sub.5 CH.sub.2 Q-Val                                             17 2-naphthylmethyl Cbz-Asn                                                   18 2-naphthylmethyl Q-Asn                                                     19 2-naphthylmethyl Cbz                                                       20 n-Bu Cbz-Val                                                               21 n-Bu Q-Val                                                                 22 n-Bu Q-Ile                                                                 23 n-Bu Cbz-t-BuGly                                                           24 n-BU Q-t-BuGly                                                             25 p-F(C.sub.6 H.sub.4)CH.sub.2 Q-Asn                                         26 p-F(C.sub.6 H.sub.4)CH.sub.2 Cbz                                           27 p-F(C.sub.6 H.sub.4)CH.sub.2 Cbz-Asn                                       28 C.sub.6 H.sub.5 CH.sub.2 Cbz-propargylglycine                              29 C.sub.6 H.sub.5 CH.sub.2 Q-propargylglycine                                30 C.sub.6 H.sub.5 CH.sub.2                                                 ______________________________________                                         acetylpropargylglycine                                                   

                  TABLE 8                                                         ______________________________________                                          #STR266##                                                                     Entry      R.sup.3       R.sup.4                                            ______________________________________                                        1        --CH.sub.2 CH(CH.sub.3).sub.2                                                               --C(CH.sub.3).sub.2                                       - 2 --CH.sub.2 CH.sub.2 CH(CH.sub.3).sub.2                                                          #STR267##                                               - 3 --CH.sub.2 CH.sub.2 CH(CH.sub.3).sub.2                                                          #STR268##                                               - 4 --CH.sub.2 CH.sub.2 CH(CH.sub.3).sub.2                                                          #STR269##                                               - 5 --CH.sub.2 CH.sub.2 CH(CH.sub.3).sub.2                                                         ##STR270##                                            ______________________________________                                    

                                      TABLE 9                                     __________________________________________________________________________      #STR271##                                                                   Entry   R                        R.sup.1                                      __________________________________________________________________________       1                                                                                                             --CH.sub.3                                    -  2                                                                                                          --CH.sub.3                                    -  3                                                                                                          --CH(CH.sub.3).sub.2                          -  4                                                                                                          --CH(CH.sub.3).sub.2                          -  5                                                                                                          --C(CH.sub.3).sub.3                           -  6                                                                                                          --CH.sub.3                                    -  7                                                                                                          --CH.sub.3                                    -  8                                                                                                          --CH.sub.3                                    -  9                                                                                                          --CH.sub.3                                    - 10                                                                                                          --CH.sub.3                                    - 11                                                                                                          --CH.sub.3                                    - 12                                                                                                          --CH.sub.3                                    - 13                                                                                                          --CH.sub.3                                    - 14                                                                                                          --CH.sub.3                                    -                                                                          15                                                                                ##STR286##                                                                16                                                                             ##STR287##                                                                   __________________________________________________________________________

                                      TABLE 10                                    __________________________________________________________________________      #STR288##                                                                   Entry R.sup.1                                                                            R.sup.1 '                                                                           R.sup.1 "                                                                           R                                                      __________________________________________________________________________      1 H H H                                                                                              #STR289##                                               - 2 H H H                                                                                           #STR290##                                               - 3 H CH.sub.3 H                                                              -                                                                                                   #STR291##                                               -                                                                            4 H CH.sub.3 CH.sub.3                                                                                #STR292##                                               - 5 H H CO.sub.2 CH.sub.3                                                                           #STR293##                                               - 6 H H H                                                                     -                                                                                                   #STR294##                                               -                                                                            7 H H H                                                                                              #STR295##                                               - 8 H H CONH.sub.2 Cbz                                                       9 H H CONH.sub.2 2-quinolinylcarbonyl                                       __________________________________________________________________________

                  TABLE 11                                                        ______________________________________                                          #STR296##                                                                     Entry       R             R'      X                                         ______________________________________                                        1         R═H       R'═H  X═H                                       2 R═Me R'═Me X═H                                                  3 R═H R'═Me X═H                                                   4 R═Me R'═Ne X═F                                                  5 R═H R'═Me X═F                                                   6 R═Cbz R'═Me X═H                                                 7 R═H R'═Bz X═H                                                   8 R+R'═pyrrole X═H                                                  ______________________________________                                    

                  TABLE 12                                                        ______________________________________                                          #STR297##                                                                     Entry         Acyl Group (R)                                                ______________________________________                                        1           benzyloxycarbonyl                                                   2 tert-butoxycarbonyl                                                         3 acetyl                                                                      4 2-quinoylcarbonyl                                                           5 phenoxyacetyl                                                               6 benzoyl                                                                     7 methyloxaloyl                                                               8 pivaloyl                                                                    9 trifluoracetyl                                                              10 bromoacetyl                                                                11 hydroxyacetyl                                                              12 morpholinylacetyl                                                          13 N,N-dimethylaminoacetyl                                                    14 N-benzylaminoacetyl                                                        15 N-phenylaminoacetyl                                                        16 N-benzyl-N-methylaminoacetyl                                               17 N-methyl-N-(2-hydroxyethyl)aminoacetyl                                     18 N-methylcarbamoyl                                                          19 3-methylbutyryl                                                            20 N-isobutylcarbamoyl                                                        21 succinoyl (3-carboxypropionyl)                                             22 carbamoyl                                                                  23 N-(2-indanyl)aminoacetyl                                                 ______________________________________                                    

                                      TABLE 13                                    __________________________________________________________________________      #STR298##                                                                      -                                                                          Entry                                                                             R.sup.3             R.sup.4                                               __________________________________________________________________________    1   --CH.sub.3          --n-Butyl                                               2 --i-Butyl --CH.sub.3                                                        3 --i-Butyl --n-Butyl                                                         4 --i-Propyl --n-Butyl                                                        5 --C.sub.6 H.sub.5 --n-Butyl                                                  - 6                                                                                                  --n-Butyl                                              - 7                                                                                                  --n-Butyl                                              - 8                                                                                                  --n-Butyl                                              - 9 --i-Butyl --n-Propyl                                                     10 --i-Butyl --CH.sub.2 CH(CH.sub.3).sub.2                                     - 11                                                                                                 --n-Butyl                                              - 12                                                                                                 --i-Propyl                                             - 13                                                                                                 --CH.sub.2 CH.sub.2 CH(CH.sub.3).sub.2                 - 14 i-Butyl --CH.sub.2 CH.sub.3                                             15 i-Butyl --CH(CH.sub.3).sub.2                                                - 16 i-Butyl                                                                                         #STR305##                                              - 17                                                                                                 --(CH.sub.2).sub.2 CH(CH.sub.3).sub.2                  - 18 (CH.sub.2).sub.2 CH(CH.sub.3).sub.2 --CH(CH.sub.3).sub.2                19 i-Butyl --CH(CH.sub.3).sub.2                                               20 i-Butyl --C(CH.sub.3).sub.3                                                 - 21                                                                                                 --C(CH.sub.3).sub.3                                    - 22 --(CH.sub.2).sub.2 CH(CH.sub.3).sub.2 --C(CH.sub.3).sub.3                                      23 --CH.sub.2 C6H5 --C(CH.sub.3).sub.3                 24 --(CH.sub.2).sub.2 C.sub.6 H.sub.5 --C(CH.sub.3).sub.3                     25 n-Butyl --C(CH.sub.3).sub.3                                                26 n-Pentyl --C(CH.sub.3).sub.3                                               27 n-Hexyl --C(CH.sub.3).sub.3                                                 - 28                                                                                                 --C(CH.sub.3).sub.3                                    - 29 --CH.sub.2 C(CH.sub.3).sub.3 --C(CH.sub.3).sub.3                         - 30                                                                                                 --C(CH.sub.3).sub.3                                    - 31 --CH.sub.2 C.sub.6 H.sub.5 OCH.sub.3 (para) --C(CH.sub.3).sub.3                                 - 32                                                                          --C(CH.sub.3).sub.3                                    - 33                                                                                                 --C(CH.sub.3).sub.3                                    - 34 --(CH.sub.2).sub.2 C(CH.sub.3).sub.3 --C(CH.sub.3).sub.3                35 --(CH.sub.2).sub.4 OH --C(CH.sub.3).sub.3                                   - 36                                                                                                 --C(CH.sub.3).sub.3                                    - 37                                                                                                 --C(CH.sub.3).sub.3                                    - 38 --CH.sub.2 CH(CH.sub.3).sub.2 --C.sub.6 H.sub.5                         39 i-amyl --CH.sub.2 C(CH.sub.3).sub.3                                         - 40                                                                                                 --CH.sub.2 C(CH.sub.3).sub.3                           - 41                                                                                                 --CH.sub.2 C(CH.sub.3).sub.3                           - 42 i-butyl --CH.sub.2 C(CH.sub.3).sub.3                                    43 --CH.sub.2 Ph --Ph                                                          - 44                                                                                                 --Ph 16##                                              - 45                                                                                                 --Ph 17##                                              - 46                                                                                                 --Ph 18##                                              - 47                                                                                                 --Ph 19##                                              - 48                                                                                                 --Ph 20##                                              - 49 --CH.sub.2 CH═CH.sub.2 --Ph                                          - 50                                                                                                 --Ph 21##                                              - 51                                                                                                 --Ph 22##                                              - 52 --CH.sub.2 CH.sub.2 Ph --Ph                                             53 --CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 OH --Ph                              54 --CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2 --Ph                                  - 55                                                                                                 --Ph 23##                                              - 56 --CH.sub.3 --Ph                                                         57 --CH.sub.2 CH.sub.2 CH.sub.2 SCH.sub.3 --Ph                                58 --CH.sub.2 CH.sub.2 CH.sub.2 S(O).sub.2 CH.sub.3 --Ph                       - 59 --CH.sub.2 CH.sub.2 CH(CH.sub.3).sub.2                                                          #STR324##                                              - 60 --CH.sub.2 CH.sub.2 CH(CH.sub.3).sub.2                                                          #STR325##                                              - 61 --CH.sub.2 CH.sub.2 CH(CH.sub.3).sub.2 --CH.sub.2 CH.sub.2                                    CH.sub.3                                                62 --CH.sub.2 CH.sub.2 CH(CH.sub.3).sub.2 --CH.sub.3                           - 63 --CH.sub.2 CH.sub.2 CH(CH.sub.3).sub.2                                                          #STR326##                                              - 64 --CH.sub.2 CH.sub.2 CH(CH.sub.3).sub.2                                                          #STR327##                                              - 65 --CH.sub.2 CH.sub.2 CH(CH.sub.3).sub.2                                                          #STR328##                                              - 66 --CH.sub.2 CH.sub.2 CH(CH.sub.3).sub.2                                                          #STR329##                                              - 67 --CH.sub.2 CH.sub.2 CH(CH.sub.3).sub.2                                                          #STR330##                                              - 68 --CH.sub.2 CH.sub.2 CH(CH.sub.3).sub.2                                                          #STR331##                                              - 69 --CH.sub.2 CH.sub.2 CH(CH.sub.3).sub.2                                                          #STR332##                                              - 70 --CH.sub.2 CH.sub.2 CH(CH.sub.3).sub.2                                                          #STR333##                                              - 71 --CH.sub.2 CH.sub.2 CH(CH.sub.3).sub.2                                                          #STR334##                                              - 72 --CH.sub.2 CH.sub.2 CH(CH.sub.3).sub.2                                                          #STR335##                                              - 73 --CH.sub.2 CH.sub.2 CH(CH.sub.3).sub.2                                                          #STR336##                                              - 74 --CH.sub.2 CH.sub.2 CH(CH.sub.3).sub.2                                                          #STR337##                                              - 75 --CH.sub.2 CH(CH.sub.3).sub.2                                                                   #STR338##                                              - 76 --CH.sub.2 CH(CH.sub.3).sub.2                                                                   #STR339##                                              - 77 --CH.sub.2 CH(CH.sub.3).sub.2                                                                   #STR340##                                              - 78 --CH.sub.2 CH(CH.sub.3).sub.2                                                                   #STR341##                                              - 79 --CH.sub.2 CH.sub.2 CH.sub.3                                                                    #STR342##                                              - 80 --CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                          ##STR343##                                           __________________________________________________________________________     .sup.a benzyloxycarbonyl                                                      .sup.b 2quinolinylcarbonyl                                               

                                      TABLE 14                                    __________________________________________________________________________      #STR344##                                                                      -                                                                          Entry    R.sup.1        R.sup.3                                               __________________________________________________________________________    1        C(CH.sub.3).sub.3                                                                            CH.sub.2 CH.sub.2 CH(CH.sub.3).sub.2                    2 CH.sub.2 C.tbd.CH CH.sub.2 CH.sub.2 CH(CH.sub.3).sub.2                      3 C(CH.sub.3).sub.2 (SCH.sub.3) CH.sub.2 CH.sub.2 CH(CH.sub.3).sub.2                                 4 C(CH.sub.3).sub.2 (S[O]CH.sub.3) CH.sub.2                                  CH.sub.2 CH(CH.sub.3).sub.2                             5 C(CH.sub.3).sub.2 (S[O].sub.2 CH.sub.3) CH.sub.2 CH.sub.2 CH(CH.sub.3)                            .sub.2                                                  6 C(CH.sub.3).sub.3 CH.sub.2 CH(CH.sub.3).sub.2                                - 7 C(CH.sub.3).sub.3                                                                                #STR345##                                              - 8 CH(CH.sub.3).sub.2 CH.sub.2 CH(CH.sub.3).sub.2                           9 CH(CH.sub.2 CH.sub.3) (CH.sub.3) CH.sub.2 CH(CH.sub.3).sub.2              __________________________________________________________________________

                  TABLE 14A                                                       ______________________________________                                          #STR346##                                                                     Entry         R.sup.1    R.sup.3                                            ______________________________________                                          1 C(CH.sub.3)SCH.sub.3 CH.sub.2 CH.sub.2 CH(CH.sub.3).sub.2                 ______________________________________                                    

                                      TABLE 15                                    __________________________________________________________________________      #STR347##                                                                     A                                                                           __________________________________________________________________________                                                     #STR348##                                                                     #STR349##                                                                     #STR350##                                                                     #STR351##                       -                                                                                                                            STR352##                                                                     #STR353##                                                                     #STR354##                       -                                                                                                                           #STR355##                                                                     #STR356##                                                                     #STR357##                                                                     #STR358##                       -                                                                                                                           #STR359##                                                                     #STR360##                                                                     #STR361##                       -                                                                                                                           #STR362##                                                                     #STR363##                                                                     #STR364##                       -                                                                                                                           #STR365##                                                                     #STR366##                                                                     #STR367##                       -                                                                                                                           #STR368##                                                                     #STR369##                       -                                                                                                                           #STR370##                                                                     #STR371##                                                                    ##STR372##                    __________________________________________________________________________

                  TABLE 16                                                        ______________________________________                                          #STR373##                                                                       A                         R                                               ______________________________________                                                                    H or CH##                                                                   .sub.3                                                 -                                                                                                      H or CH.sub.3                                        -                                                                                                      H or CH.sub.3                                        -                                                                                                      H or CH.sub.3                                        -                                                                                                      H or CH.sub.3                                        -                                                                                                      H or CH.sub.3                                        -                                                                                                      H or CH.sub.3                                        -                                                                                                      H or CH.sub.3                                        -                                                                                                      H or CH.sub.3                                        -                                                                                                      H or CH.sub.3                                        -                                                                                                      H or CH.sub.3                                        -                                                                                                      H or CH.sub.3                                        -                                                                                                      H or CH.sub.3                                        -                                                                                                      H or CH.sub.3                                        -                                                                                                      H or CH.sub.3                                        -                                                                                                      H or CH.sub.3                                        -                                                                                                      H or CH.sub.3                                     ______________________________________                                    

                  TABLE 17                                                        ______________________________________                                          #STR391##                                                                        A Group         B Group                                                  ______________________________________                                                           #STR392##                                                                     #STR393##                                                     -                                                                                             #STR394##                                                                     #STR395##                                                     -                                                                                             #STR396##                                                                     #STR397##                                                     -                                                                                             #STR398##                                                     -                                                                                             #STR399##                                                     -                                                                                             #STR400##                                                     -                                                                                            ##STR401##                                                  ______________________________________                                    

                  TABLE 17A                                                       ______________________________________                                          #STR402##                                                                     A Group       B Group                                                       ______________________________________                                                      n TR403##                                                                   = 0,1, or 2                                                          -                                                                                        R' = OH, methoxy, benzyloxy,  --C(NH.sub.2)═NOH,                        --C(NH.sub.2)═NH                                                 -                                                                                        R" = H or lower alkyl.                                             -                                                                                                      #STR406##                                                                     #STR407##                                                                     #STR408##                                            -                                                                                                      #STR409##                                                                     #STR410##                                                                     #STR411##                                            -                                                                                                      #STR412##                                                                     #STR413##                                                                     #STR414##                                            -                                                                                                      #STR415##                                            -                                                                                                      #STR416##                                            -                                                                                                     ##STR417##                                         ______________________________________                                    

                                      TABLE 17B                                   __________________________________________________________________________                 R = H or OH                                                        R.sup.1 = CH.sub.3, NH.sub.2, F, Cl or Br                                     R.sup.2 = H or CH.sub.3                                                     __________________________________________________________________________      #STR418##                                                                      -                                                                            #STR419##                                                                      -                                                                            #STR420##                                                                      -                                                                            #STR421##                                                                   __________________________________________________________________________

                                      TABLE 17B-1                                 __________________________________________________________________________      #STR422##                                                                      -                                                                            #STR423##                                                                      -                                                                            #STR424##                                                                      -                                                                            #STR425##                                                                   __________________________________________________________________________

                                      TABLE 17B-2                                 __________________________________________________________________________      #STR426##                                                                      -                                                                            #STR427##                                                                   __________________________________________________________________________

EXAMPLE 19

The compounds of the present invention are effective HIV proteaseinhibitors. Utilizing an enzyme assay as described below, the compoundsset forth in the examples herein disclosed inhibited the HIV enzyme. Thepreferred compounds of the present invention and their calculated IC₅₀(inhibiting concentration 50%, i.e., the concentration at which theinhibitor compound reduces enzyme activity by 50%) values are shown inTables 18 through 21. The enzyme method is described below. Thesubstrate is 2-Ile-Nle-Phe(p-NO₂)-Gln-ArgNH₂. The positive control isMVT-101 (Miller, M. et al, Science, 246, 1149 (1989)] The assayconditions are as follows:

Assay Buffer:

20 mM sodium phosphate, pH 6.4

20% glycerol

1 mM EDTA

1 mM DTT

0.1% CHAPS.

The above described substrate is dissolved in DMSO, then diluted 10 foldin assay buffer. Final substrate concentration in the assay is 80 μM.

HIV protease is diluted in the assay buffer to a final enzymeconcentration of 12.3 nanomolar, based on a molecular weight of 10,780.

The final concentration of DMSO is 14% and the final concentration ofglycerol is 18%. The test compound is dissolved in DMSO and diluted inDMSO to 10× the test concentration; 10 μl of the enzyme preparation isadded, the materials mixed and then the mixture is incubated at ambienttemperature for 15 minutes. The enzyme reaction is initiated by theaddition of 40 μl of substrate. The increase in fluorescence ismonitored at 4 time points (0, 8, 16 and 24 minutes) at ambienttemperature. Each assay is carried out in duplicate wells.

The preceding examples can be repeated with similar success bysubstituting the generically or specifically described reactants and/oroperating conditions of this invention for those used in the precedingexamples.

                                      TABLE 18A                                   __________________________________________________________________________    Entry                                                                            Compound                                  IC.sub.50 (namomolar)            __________________________________________________________________________      1                                                                                                                          16 R428##                         - 2                                                                                                                       1.5 429##                         - 3                                                                                                                       1.4 430##                         - 4                                                                                                                       27 R431##                         - 5                                                                                                                       19 R432##                         - 6                                                                                                                       10 R433##                         - 7                                                                                                                       3.6 434##                         - 8                                                                                                                       4.2 435##                         - 9                                                                                                                       3.5 436##                         - 10                                                                                                                      100 437##                         - 11                                                                                                                      81 R438##                         - 12                                                                                                                      20TR439##                      __________________________________________________________________________

                  TABLE 19B                                                       ______________________________________                                        Ex.      Table  Entry      IC.sub.50 (uM) or % inhib                          ______________________________________                                        6        la     1          0.011                                                6           la         2                0.010                                 6           la         3             38% @ 1 uM, 79% @ 10 uM                  6           la         4                0.016                                 6           la         5                0.10                                  6           la         6                36% @ 10 uM                           6           la         7                0.0096                                6           la         39               0.016                                 6           la         40               0.21                                  6           la         41            24% @ 1 uM, 74% @ 10 uM                  6           la         50            42% @ 1 uM, 89% @ 10 uM                  6           la         51            31% @ 1 uM, 76% @ 10 uM                  6           la         52            39% @ 1 uM, 81% @ 10 uM                  6           la         53               0.049                                 6           la         54               0.0028                                6           la         55               0.10                                  6           la         56                0.0036                               16          3           1                 0.081                               16          3           2              38% @ 0.1 uM, 90% @ 1.0 uM                                       16          3           4                                                    0.0024                                               16          3           6                 0.0018                              16          3           8                 0.003                               16          3           10                0.0025                              16          3           12                0.0016                              16          4           102               0.0015                              16          5           1                 0.0014                              16          5           14                0.0022                              16          5           22                0.0018                              16          5           33                0.0044                              16          5           34                0.0020                              16          7           31                0.0028                              16          7           32                0.0015                              16          11         1                 0.13                                 16          11         9              41% @ 0.1 uM, 86% @ 1 uM                16          12         10                0.0033                               16          14         3                 0.0049                               16          14         10                0.0032                             ______________________________________                                    

                  TABLE 20                                                        ______________________________________                                        Table       Entry  IC.sub.50 (uM) or % inhibtion                              ______________________________________                                        1A          3      0.02                                                         5A 1 0.04                                                                     5A 3 0.02                                                                     5A 4 0.01                                                                     5A 5 0.026                                                                    5A 6 0.023                                                                    5A 7 0.007                                                                    5A 9 0.067                                                                    5A 11 0.018                                                                   5A 12 0.006                                                                   5A 13 0.0098                                                                  5A 14 0.049                                                                   5A 16 0.008                                                                   5A 17 59% @ 10 μM                                                          5A 18 0.13                                                                    5A 19 0.092                                                                   5A 20 85% @ 1 μM                                                           5A 22 63% @ 1 μM                                                           5A 24 0.047                                                                   5A 25 0.014                                                                   5A 26 0.005                                                                   5A 28 0.015                                                                   5A 29 0.19                                                                    5A 30 0.03                                                                    5A 31 0.02                                                                  ______________________________________                                    

EXAMPLE 20

The effectiveness of the compounds listed in Table 15 were determined inthe above-described enzyme assay and in a CEM cell assay.

The HIV inhibition assay method of acutely infected cells is anautomated tetrazolium based calorimetric assay essentially that reportedby Pauwles et al, J. Virol. Methods, 20, 309-321 (1988). Assays wereperformed in 96-well tissue culture plates. CEM cells, a CD4+ cell line,were grown in RPMI-1640 medium (Gibco) supplemented with a 10% fetalcalf serum and were then treated with polybrene (2 μg/ml). An 80 μlvolume of medium containing 1×10⁴ cells was dispensed into each well ofthe tissue culture plate. To each well was added a 100 μl volume of testcompound dissolved in tissue culture medium (or medium without testcompound as a control) to achieve the desired final concentration andthe cells were incubated at 37° C. for 1 hour. A frozen culture of HIV-1was diluted in culture medium to a concentration of 5×10⁴ TCID₅₀ per ml(TCID₅₀ =the dose of virus that infects 50% of cells in tissue culture),and a 20 μL volume of the virus sample (containing 1000 TCID₅₀ of virus)was added to wells containing test compound and to wells containing onlymedium (infected control cells). Several wells received culture mediumwithout virus (uninfected control cells). Likewise, the intrinsictoxicity of the test compound was determined by adding medium withoutvirus to several wells containing test compound. In summary, the tissueculture plates contained the following experiments:

    ______________________________________                                                Cells          Drug   Virus                                           ______________________________________                                        1.      +              -      -                                                 2. + + -                                                                      3. + - +                                                                      4. + + +                                                                    ______________________________________                                    

In experiments 2 and 4 the final concentrations of test compounds were1, 10, 100 and 500 μg/ml. Either azidothymidine (AZT) or dideoxyinosine(ddI) was included as a positive drug control. Test compounds weredissolved in DMSO and diluted into tissue culture medium so that thefinal DMSO concentration did not exceed 1.5% in any case. DMSO was addedto all control wells at an appropriate concentration.

Following the addition of virus, cells were incubated at 37° C. in ahumidified, 5% CO₂ atmosphere for 7 days. Test compounds could be addedon days 0, 2 and 5 if desired. On day 7, post-infection, the cells ineach well were resuspended and a 100 μl sample of each cell suspensionwas removed for assay. A 20 μL volume of a 5 mg/ml solution of3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) wasadded to each 100 μL cell suspension, and the cells were incubated for 4hours at 27° C. in a 5% CO₂ environment. During this incubation, MTT ismetabolically reduced by living cells resulting in the production in thecell of a colored formazan product. To each sample was added 100 μl of10% sodium dodecylsulfate in 0.01 N HCl to lyse the cells, and sampleswere incubated overnight. The absorbance at 590 nm was determined foreach sample using a Molecular Devices microplate reader. Absorbancevalues for each set of wells is compared to assess viral controlinfection, uninfected control cell response as well as test compound bycytotoxicity and antiviral efficacy.

                                      TABLE 21                                    __________________________________________________________________________                                                     IC.sub.50                                                                         EC.sub.50                                                                          TD.sub.50                                                                      Entry Compound                                                               (nM) (nM)           __________________________________________________________________________                                                              (nM)                  1                                                                                                                                       16 55 27                                                                      - 2                                                                           1 5 203                                                                     #       - 3                                                                     1 11 780                                                                      - 4                                                                           27 64 28                                                                      - 5                                                                           19 88 11                                                                      - 6                                                                           >100 380 425                                                                  - 7                                                                           3 25 39                                                                     #       - 8                                                                     85 1200 24                                                                    - 9                                                                           53 398 15                                                                     - 10                                                                          45 700 12                                                                     - 11                                                                          3 11 54                                                                     #       - 12                                                                    2 12 7.5                                                                      - 13                                                                          3 <16                                                                       2##       - 14                                                                  4 15 55,000                                                                   - 15                                                                          5 38 54##            - 16                                                                                                                                   9 80 62.000                                                                   - 17                                                                          4 5 59,000                                                                    - 18                                                                          8 TR457##            - 19                                                                                                                                   4 TR458##            - 20                                                                                                                                   4 TR459##            - 21                                                                                                                                   73 R460##            - 22                                                                                                                                   15 18 31,000                                                                  - 23                                                                          2 TR462##            - 24                                                                                                                                   3 TR463##            - 25                                                                                                                                   60 120                                                                      167,000                                                                         - 26                                                                          #STR465##            - 27                                                                                                                                   5 177 300,000        - 28                                                                                                                                   14 76 213,000        - 29                                                                                                                                   5 105 196,000        - 30                                                                                                                                   6 154 154,000        - 31                                                                                                                                   10 R470##            - 32                                                                                                                                   5 98 17,000                                                                   - 33                                                                          18 68                                                                       2##       - 34                                                                  67 188                                                                      ##       - 35                                                                   #STR474##            - 36                                                                                                                                   310 898                                                                     #       - 37                                                                    7 <20                                                                       6##       - 38                                                                  4 1,100                                                                     #       - 39                                                                    16 269                                                                      ##       - 40                                                                   3 TR479##            - 41                                                                                                                                   3 11 80##            - 42                                                                                                                                   2 TR481##            - 43                                                                                                                                   4 TR482##            - 44                                                                                                                                   4 8 483##            - 45                                                                                                                                   2 5 484##            - 46                                                                                                                                   2 TR485##            - 47                                                                                                                                   3 TR486##            -  - 48                                                                                                                                17 210                                                                      ##       - 49                                                                   6 <20                                                                       8##       - 50                                                                  14 R489##            - 51                                                                                                                                   9 TR490##            - 52                                                                                                                                   >100 91##            - 53                                                                                                                                   21 R492##            - 54                                                                                                                                   10 R493##            - 55                                                                                                                                   37TR494##         __________________________________________________________________________

The compounds of the present invention are effective antiviral compoundsand, in particular, are effective retroviral inhibitors as shown above.Thus, the subject compounds are effective HIV protease inhibitors. It iscontemplated that the subject compounds will also inhibit otherretroviruses such as other lentiviruses in particular other strains ofHIV, e.g. HIV-2, human T-cell leukemia virus, respiratory syncitialvirus, simia immunodeficiency virus, feline leukemia virus, felineimmuno-deficiency virus, hepadnavirus, cytomegalovirus and picornavirus.Thus, the subject compounds are effective in the treatment and/orproplylaxis of retroviral infections.

The subject compounds are also effective in preventing the growth ofretroviruses in a solution. Both human and animal cell cultures, such asT-lymphocyte cultures, are utilized for a variety of well knownpurposes, such as research and diagnostic procedures includingcalibrators and controls. Prior to and during the growth and storage ofa cell culture, the subject compounds may be added to the cell culturemedium at an effective concentration to prevent the unexpected orundesired replication of a retrovirus that may inadvertently orunknowingly be present in the cell culture. The virus may be presentoriginally in the cell culture, for example HIV is known to be presentin human T-lymphocytes long before it is detectable in blood, or throughexposure to the virus. This use of the subject compounds prevents theunknowing or inadvertent exposure of a potentially lethal retrovirus toa researcher or clinician.

Compounds of the present invention can possess one or more asymmetriccarbon atoms and are thus capable of existing in the form of opticalisomers as well as in the form of racemic or nonracemic mixturesthereof. The optical isomers can be obtained by resolution of theracemic mixtures according to conventional processes, for example byformation of diastereoisomeric salts by treatment with an opticallyactive acid or base. Examples of appropriate acids are tartaric,diacetyltartaric, dibenzoyltartaric, ditoluoyltartaric andcamphorsulfonic acid and then separation of the mixture ofdiastereoisomers by crystallization followed by liberation of theoptically active bases from these salts. A different process forseparation of optical isomers involves the use of a chiralchromatography column optimally chosen to maximize the separation of theenantiomers. Still another available method involves synthesis ofcovalent diastereoisomeric molecules by reacting compounds of Formula Iwith an optically pure acid in an activated form or an optically pureisocyanate. The synthesized diastereoisomers can be separated byconventional means such as chromatography, distillation, crystallizationor sublimation, and then hydrolyzed to deliver the enantiomerically purecompound. The optically active compounds of Formula I can likewise beobtained by utilizing optically active starting materials. These isomersmay be in the form of a free acid, a free base, an ester or a salt.

The compounds of the present invention can be used in the form of saltsderived from inorganic or organic acids. These salts include but are notlimited to the following: acetate, adipate, alginate, citrate,aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate,camphorsulfonate, digluconate, cyclopentanepropionate, dodecylsulfate,ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate,heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide,hydroiodide, 2-hydroxy-ethanesulfonate, lactate, maleate,methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmoate,pectinate, persulfate, 3-phenylpropionate, picrate, pivalate,propionate, succinate, tartrate, thiocyanate, tosylate, mesylate andundecanoate. Also, the basic nitrogen-containing groups can bequaternized with such agents as lower alkyl halides, such as methyl,ethyl, propyl, and butyl chloride, bromides, and iodides; dialkylsulfates like dimethyl, diethyl, dibutyl, and diamyl sulfates, longchain halides such as decyl, lauryl, myristyl and stearyl chlorides,bromides and iodides, aralkyl halides like benzyl and phenethylbromides, and others. Water or oil-soluble or dispersible products arethereby obtained.

Examples of acids which may be employed to form pharmaceuticallyacceptable acid addition salts include such inorganic acids ashydrochloric acid, sulphuric acid and phosphoric acid and such organicacids as oxalic acid, maleic acid, succinic acid and citric acid. Otherexamples include salts with alkali metals or alkaline earth metals, suchas sodium, potassium, calcium or magnesium or with organic bases.

Total daily dose administered to a host in single or divided doses maybe in amounts, for example, from 0.001 to 10 mg/kg body weight daily andmore usually 0.01 to 1 mg. Dosage unit compositions may contain suchamounts of submultiples thereof to make up the daily dose.

The amount of active ingredient that may be combined with the carriermaterials to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration.

The dosage regimen for treating a disease condition with the compoundsand/or compositions of this invention is selected in accordance with avariety of factors, including the type, age, weight, sex, diet andmedical condition of the patient, the severity of the disease, the routeof administration, pharmacological considerations such as the activity,efficacy, pharmacokinetic and toxicology profiles of the particularcompound employed, whether a drug delivery system is utilized andwhether the compound is administered as part of a drug combination Thus,the dosage regimen actually employed may vary widely and therefore maydeviate from the preferred dosage regimen set forth above.

The compounds of the present invention may be administered orally,parenterally, by inhalation spray, rectally, or topically in dosage unitformulations containing conventional nontoxic pharmaceuticallyacceptable carriers, adjuvants, and vehicles as desired. Topicaladministration may also involve the use of transdermal administrationsuch as transdermal patches or iontophoresis devices. The termparenteral as used herein includes subcutaneous injections, intravenous,intramuscular, intrasternal injection, or infusion techniques.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectable solutionor suspension in a nontoxic parenterally acceptable diluent or solvent,for example, as a solution in 1,3-butanediol. Among the acceptablevehicles and solvents that may be employed are water, Ringer's solution,and isotonic sodium chloride solution In addition, sterile, fixed oilsare conventionally employed as a solvent or suspending medium. For thispurpose any bland fixed oil may be employed including synthetic mono- ordiglycerides. In addition, fatty acids such as oleic acid find use inthe preparation of injectables.

Suppositories for rectal administration of the drug can be prepared bymixing the drug with a suitable nonirritating excipient such as cocoabutter and polyethylene glycols which are solid at ordinary temperaturesbut liquid at the rectal temperature and will therefore melt in therectum and release the drug.

Solid dosage forms for oral administration may include capsules,tablets, pills, powders, and granules. In such solid dosage forms, theactive compound may be admixed with at least one inert diluent such assucrose lactose or starch. Such dosage forms may also comprise, as innormal practice, additional substances other than inert diluents, e.g.,lubricating agents such as magnesium stearate. In the case of capsules,tablets, and pills, the dosage forms may also comprise buffering agents.Tablets and pills can additionally be prepared with enteric coatings.

Liquid dosage forms for oral administration may include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups, and elixirscontaining inert diluents commonly used in the art, such as water. Suchcompositions may also comprise adjuvants, such as wetting agents,emulsifying and suspending agents, and sweetening, flavoring, andperfuming agents.

While the compounds of the invention can be administered as the soleactive pharmaceutical agent, they can also be used in combination withone or more immunomodulators, antiviral agents or other antiinfectiveagents. For example, the compounds of the invention can be administeredin combination with AZT, DDI, DDC or with glucosidase inhibitors, suchas N-butyl-1-deoxynojirimycin or prodrugs thereof, for the prophylaxisand/or treatment of AIDS. When administered as a combination, thetherapeutic agents can be formulated as separate compositions which aregiven at the same time or different times, or the therapeutic agents canbe given as a single composition.

The foregoing is merely illustrative of the invention and is notintended to limit the invention to the disclosed compounds. Variationsand changes which are obvious to one skilled in the art are intended tobe within the scope and nature of the invention which are defined in theappended claims.

From the foregoing description, one skilled in the art can easilyascertain the essential characteristics of this invention, and withoutdeparting from the spirit and scope thereof, can make various changesand modifications of the invention to adapt it to various usages andconditions.

What is claimed is:
 1. A compound represented by the formula: ##STR495##or a pharmaceutically acceptable salt thereof wherein R² is an alkyl,aryl, cycloalkyl, cycloalkylalkyl or aralkyl radical, which radical isoptionally substituted with a radical selected from the group consistingof alkyl, halo, nitro, cyano, CF₃, --OR⁹, and --SR⁹ radicals, wherein R⁹is hydrogen or alkyl radicals;R³ is alkyl, haloalkyl, alkenyl, alkynyl,hydroxyalkyl, alkoxyalkyl, alkylthioalkyl, alkylsulfonylalkyl,cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heteroaryl,heterocycloalkylalkyl, aryl, aralkyl or heteroaralkyl radicals; R⁴ isheterocycloalkyl, heteroaryl or aryl radicals; Y is O or S; and A isheterocycloalkyl, heterocycloalkoxy, heterocycloalkylalkyl,heterocycloalkylalkoxy, heteroaralkyl, heteroaralkoxy, heteroaryloxy orheteroaryl radicals; and wherein alkyl, alone or in combination, is astraight-chain or branched-chain alkyl radical containing 1 to 8 carbonatoms; alkenyl, alone or in combination, is a straight-chain orbranched-chain hydrocarbon radial having at least one double bond andcontaining 2 to 8 carbon atoms; alkynyl, alone or in combination, is astraight-chain or branched chain hydrocarbon radical having at least onetriple bond and containing 2 to 10 carbon atoms; aryl, alone or incombination, is an unsubstituted phenyl or naphthyl radical or a phenylor naphthyl radical substituted with alkyl, alkoxy, halogen, hydroxy,amino, alkylamino, dialkylamino, nitro, cyano, carboxy, alkoxycarbonyl,amido, alkylamido, dialkylamido, trifluoromethyl, methylthio,methylsulfinyl or methylsulfonyl radicals; cycloalkyl, alone or incombination, is a saturated or partially saturated monocyclic, bicyclicor tricyclic alkyl radical wherein each cyclic moiety contains 3 to 8carbon atoms; heterocycloalkyl, alone or in combination, is amonocyclic, bicyclic or tricyclic heterocycle radical having 1-4nitrogen, nitrogen oxide, oxygen, sulphur, sulfone or sulfoxideheteroatom ring members, optionally benz-fused and optionallysubstituted on one or more carbon atoms by halogen, alkyl, alkoxy,hydroxy, oxo, aryl or aralkyl radicals, or on a secondary nitrogen atomby hydroxy, alkyl, aralkoxycarbonyl, alkanoyl, phenyl or phenylalkylradicals; and heteroaryl, alone or in combination, is an aromaticheterocycloalkyl, optionally substituted with respect to aryl andheterocycloalkyl radicals.
 2. Compound of claim 1 or a pharmaceuticallyacceptable salt thereof whereinR² represents alkyl, cycloalkylalkyl oraralkyl radicals, which radicals are optionally substituted with alkyl,halogen or --OR⁹ radicals, wherein R⁹ represents hydrogen or alkylradicals; and R³ is alkyl, alkenyl, alkynyl, hydroxyalkyl, alkoxyalkyl,alkylthioalkyl, alkylsulfonylalkyl, cycloalkyl, cycloalkylalkyl,heterocycloalkylalkyl, aryl, aralkyl or heteroaralkyl radicals; whereinheterocycloalkyl, alone or in combination, is a 5-6 ring memberedmonocyclic heterocycle radical having 1-4 nitrogen, nitrogen oxide,oxygen, sulphur, sulfone or sulfoxide heteroatom ring members,optionally benz-fused and optionally substituted on one or more carbonatoms by halogen, alkyl, alkoxy, hydroxy, oxo, aryl or aralkyl radicals,or on a secondary nitrogen atom by hydroxy, alkyl, aralkoxycarbonyl,alkanoyl, phenyl or phenylalkyl radicals; and heteroaryl, alone or incombination, is an aromatic heterocycloalkyl, optionally substitutedwith respect to aryl and heterocycloalkyl radicals.
 3. Compound of claim2 or a pharmaceutically acceptable salt thereof whereinA isheterocycloalkyl, heterocycloalkoxy, heterocycloalkylalkyl,heteroaralkoxy or heteroaryl radicals; R³ represents alkyl, cycloalkylor cycloalkylalkyl radicals; and R⁴ is heterocycloalkyl or arylradicals; wherein alkyl, alone or in combination, is a straight-chain orbranched-chain hydrocarbon radical containing from 1-5 carbon atoms;alkenyl, alone or in combination, is a straight-chain or branched-chainhydrocarbon radical having at least one double bond and containing from2-5 carbon atoms; alkynyl, alone or in combination, is a straight-chainor branched-chain hydrocarbon radical having at least one triple bondand containing from 2-5 carbon atoms; heterocycloalkyl, alone or incombination, is a 5-6 ring membered heterocycle or a benzfused 5-6 ringmembered heterocycle having one or two nitrogen, nitrogen oxide, oxygen,sulphur, sulfone or sulfoxide heteroatoms; and heteroaryl means anaromatic 5-6 ring membered heterocycle or an aromatic benzfused 5-6 ringmembered heterocycle having one or two nitrogen, nitrogen oxide, oxygen,sulphur or sulfone heteroatoms.
 4. Compound of claim 3 or apharmaceutically acceptable salt thereof whereinA is heterocycloalkyl orheterocycloalkoxy radicals; R² represents alkyl, cycloalkylalkyl oraralkyl radicals; R³ represents alkyl, cycloalkyl or cycloalkylalkylradicals; R⁴ is an aryl radical; and Y is O; wherein heterocycloalkyl,alone or in combination, is a 5-6 ring membered heterocycle having anoxygen, sulphur, sulfone or sulfoxide heteroatom.
 5. Compound of claim 4or a pharmaceutically acceptable salt thereof whereinA isheterocycloalkyl or heterocycloalkoxy radicals; R² represents butyl,benzyl, cyclohexylmethyl or 2-naphthylmethyl radicals; R³ representsisobutyl, isoamyl, cyclohexyl, cyclohexylmethyl, n-butyl or n-propylradicals; and R⁴ is phenyl, methoxyphenyl, cyanophenyl, chlorophenyl,hydroxyphenyl, nitrophenyl, fluorophenyl or aminophenyl radical; whereinheterocycloalkyl, alone or in combination, is a 5-6 ring memberedheterocycle having an oxygen, sulphur, sulfone or sulfoxide heteroatom.6. Compound of claim 2 or a pharmaceutically acceptable salt thereofwhereinR² is butyl, cyclohexylmethyl, benzyl, 4-fluorobenzyl ornaphthylmethyl radicals; R³ is methyl, ethyl, propyl, butyl, pentyl,hexyl, iso-butyl, iso-amyl, 3-methoxypropyl, 3-methylthiopropyl,4-methylthiobutyl, 4-methylsulfonylbutyl, 2-(1-morpholino)ethyl,4-hydroxybutyl, allyl, propargyl, cyclohexylmethyl, cyclopropylmethyl,phenyl, benzyl, 4-fluorobenzyl, 4-methoxybenzyl, 1-phenylethyl,2-phenylethyl, naphthylmethyl, 3-pyridylmethyl or 4-pyridylmethylradicals; R⁴ is phenyl, naphthyl, chlorophenyl, fluorophenyl,hydroxyphenyl, methylphenyl, methoxyphenyl, ethoxyphenyl,methylthiophenyl, methylsulfinylphenyl, methylsulfonylphenyl,acetamidophenyl, methoxycarbonylphenyl, aminophenyl,dimethylaminophenyl, nitrophenyl, trifluoromethylphenyl or thienylradicals; Y is O; and A is quinolinyl, indolyl, pyridyl, methylpyridyl,furanyl, oxazolyl, thiazolyl, pyridylmethoxy, hydroxypyridylmethoxy,aminopyridylmethoxy, pyrimidinylmethoxy, N-oxo-pyrimidinylmethoxy,thiazolylmethoxy, tetrahydrothiophenoxy, 1,1-dioxotetrahydrothiophenoxyor tetrahydrofuranoxy radicals.
 7. A compound of claim 1 whichisCarbamic acid,[2R-hydroxy-3-[(4-hydroxyphenylsulfonyl)(2-methylpropyl)amino]-1S-(phenylmethyl)propyl-,3(S)-1,1-dioxotetrahydrothiophen-3-yl-ester; Carbamic acid,[2R-hydroxy-3-[(4-methoxyphenylsulfonyl)(2-methylpropyl)amino]-1S-(phenylmethyl)propyl-,3(S)-1,1-dioxotetrahydrothiophen-3-yl-ester; Carbamic acid,[2R-hydroxy-3-[(4-methoxyyphenylsulfonyl)(2-methylpropyl)amino]-1S-(phenylmethyl)propyl-,3-S-tetrahydrothiophen-3-yl-ester; Carbamic acid,[2R-hydroxy-3-[(4-hydroxyphenylsulfonyl)(2-methylpropyl)amino]-1S-(phenylmethyl)propyl-,3-S-tetrahydrothiophen-3-yl-ester; Carbamic acid,[2R-hydroxy-3-[(4-hydroxyphenylsulfonyl)(2-methylpropyl)amino]-1S-(phenylmethyl)propyl-,3-S-tetrahydrofuran-3-yl-ester; Carbamic acid,[2R-hydroxy-3-[(4-methoxyphenylsulfonyl)(2-methylpropyl)amino]-1S-(phenylmethyl)propyl-,3-S-tetrahydrofuran-3-yl-ester; Carbamic acid,[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-,5-(thiazolyl)methyl ester; Carbamic acid,[2R-hydroxy-3-[[(4-hydroxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-,5-(thiazolyi)methyl ester; Carbamic acid,[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-,3-(6-aminopyridyl)methyl ester; Carbamic acid,[2R-hydroxy-3-[[(4-hydroxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-,3-(6-aminopyridyl)methyl ester; Carbamic acid,[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-,3-(6-hydroxypyridyl)methyl ester; Carbamic acid,[2R-hydroxy-3-[[(4-hydroxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-,5-pyrimidyimethyl ester; 4-Pyridinecarboxamide,N-[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]; Carbamic acid,[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-,3-pyridylmethyl ester; Carbamic acid,[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-,3-pyridylmethyl ester, N-oxide; Carbamic acid,[2R-hydroxy-3-[[phenylsulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-,3-pyridylmethyl ester; Carbamic acid,[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-,4-pyridylmethyl ester; Carbamic acid,[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-,4-pyridylmethyl ester, N-oxide; Carbamic acid,[2R-hydroxy-3-[[(4-chlorophenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-,3-pyridylmethyl ester; Carbamic acid,[2R-hydroxy-3-[[(4-nitrophenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-,3-pyridylmethyl ester; Carbamic acid,[2R-hydroxy-3-[[(4-fluorophenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-,3-pyridylmethyl ester; Carbamic acid,[2R-hydroxy-3-[[(4-hydroxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-,3-pyridylmethyl ester; or Carbamic acid,[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-,5-pyrimidylmethyl ester.
 8. A pharmaceutical composition comprising acompound of claim 1 and a pharmaceutically acceptable carrier.
 9. Thecompound of claim 1 wherein said heterocycloalkyl or heteroaryl isselected from optionally substituted pyrrolidinyl, piperidinyl,piperazinyl, morpholinyl, thiamorpholinyl, pyrrolyl, imidazolyls,pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, furyl, thienyl, triazolyl,oxazolyl, thiazolyl, indolyls, quinolynyls, isoquinolinyls,tetrahydroquinolinyls, 1,2,3,4-tetrahydroisoquinolinyls, quinoxalinyl,β-carbolinyl, 2-benzofurancarbonyl, and benzimidazolyls radicals.
 10. Acompound represented by the formula: ##STR496## or a pharmaceuticallyacceptable salt thereof wherein R² is an aralkyl radical;R³ is alkyl; R⁴is an aryl radical; Y is O; and A is a 5-membered ring containing oneoxygen or one sulfur atom.
 11. Compound of claim 1 wherein saidheterocycloalkyl is a 5-6 ring membered monocyclic, heterocycle radicalhaving 1-4 nitrogen, nitrogen oxide, oxygen, sulphur, sulfone orsulfoxide heteroatom ring members, optionally benzfused and optionallysubstituted on one or more carbon atoms by halogen, alkyl, alkoxy,hydroxy, oxo aryl or aralkyl radicals, or on a secondary nitrogen atomby hydroxy alkyl, aralkoxycarbonyl, alkanoyl, phenyl or phenylalkylradicals, and said heteroaryl is an aromatic heterocycloalkyl optionallybenzfused and optionally substituted.
 12. Compound of claim 11 whereinsaid heterocycloalkyl is a 5-6 ring membered heterocycle or a benzfused5-6 ring membered heterocycle having one or two nitrogen, nitrogenoxide, oxygen, sulfur, sulfone or sulfoxide heteroatoms; and saidheteroaryl is an aromatic 5-6 ring membered heterocycle or an aromaticbenzfused 5-6 ring membered heterocycle having one or two nitrogen,nitrogen oxide, oxygen sulphur or sulfone heteroatoms.